BACKGROUND: Beyond knee pain itself, the fear of movement, also known as kinesiophobia, recently has been proposed as a potential factor contributing to disability and functional limitation in patients with knee osteoarthritis (OA). Nevertheless, the available evidence on the association of kinesiophobia with patient-reported outcome measures (PROMs) in knee OA remains limited. QUESTIONS/PURPOSES: Among patients with nonoperatively treated knee OA, we asked: (1) Is kinesiophobia associated with decreased quality of life (QoL), functional outcomes, and physical activity? (2) What are the patient disease and psychosocial demographic factors associated with kinesiophobia? METHODS: This was a multicenter, cross-sectional study of 406 general orthopaedic patients from two urban, referral-based tertiary hospitals in Singapore under a single healthcare group who received nonoperative treatment for knee OA. Between July 2020 and January 2022, a total of 1541 patients were treated for knee OA nonoperatively. Based on that, 60% (923) of patients were rejected due to refusal to participate in the study, 3% (52) of patients were enrolled but did not show up for their appointments for data collection, and a further 10% (160) had incomplete data sets, leaving 26% (406) for this study's analysis. The mean age of patients was 64 ± 8 years, 69% were women, and 81% were Chinese. The level of kinesiophobia in patients was measured using the Brief Fear of Movement scale, a validated 6-item questionnaire ranging from a score of 6 to 24 to measure kinesiophobia in OA, with higher scores representing higher levels of kinesiophobia. In terms of PROMs, the QoL and functional level of patients were measured using the QoL and activities of daily living (ADL) components of the widely validated 12-item Knee Injury and Osteoarthritis Outcome Score (KOOS-12). The KOOS-12 is a questionnaire consisting of 12 items encompassing three domains (QoL, ADL, and pain), with each item ranging from 0 to 4 and higher scores representing worse outcomes. The University of California, Los Angeles (UCLA) Activity Scale was used to measure the level of physical activity in patients. The UCLA score is a descriptive 10-level activity scale ranging from a score of 1 to 10, with higher scores representing greater physical activity levels. A directed acyclic graph, which is a relationship map used to depict and visualize the confounders between the studied variables, was used to identify the confounders between kinesiophobia and PROMs (QoL, function, and physical activity). An ordinal regression model was used to explore: (1) the association between kinesiophobia (as measured using the Brief Fear of Movement scale) and PROMs (as measured using KOOS QoL, KOOS ADL, and the UCLA Activity Scale), adjusting for key confounders such as age, gender, pain, side of arthritis, OA duration/severity, and psychosocial factors (for example, depression, anxiety, and education levels), and (2) the association between kinesiophobia (Brief Fear of Movement scale) and various patient disease and psychosocial demographic factors. RESULTS: After accounting for confounders, greater kinesiophobia (higher Brief Fear of Movement scores) was associated with lower QoL (KOOS QoL score adjusted IQR OR 0.69 [95% confidence interval (CI) 0.53 to 0.90]; p = 0.007) and lower physical activity (UCLA score adjusted IQR OR 0.68 [95% CI 0.52 to 0.90]; p = 0.007); however, there was no association between kinesiophobia and function (KOOS ADL score adjusted IQR OR 0.90 [95% CI 0.70 to 1.17]; p = 0.45). After adjusting for age, gender, OA duration, pain, and BMI, higher levels of anxiety (Patient Health Questionnaire 2 [PHQ-2] anxiety score adjusted OR 2.49 [95% CI 1.36 to 4.58]; p = 0.003) and depression (PHQ-2 depression score adjusted OR 3.38 [95% CI 1.73 to 6.62]; p < 0.001) were associated with higher levels of kinesiophobia. Education level, OA disease severity, side of arthritis (unilateral versus bilateral), and history of previous injury or surgery on the knee were not associated with kinesiophobia. CONCLUSION: Clinicians should assess for kinesiophobia and other psychological comorbidities such as depression and anxiety at the point of initial evaluation and subsequent follow-up of knee OA with simple validated tools like the Brief Fear of Movement scale (kinesiophobia) in the clinic. This allows for clinicians to identify high-risk individuals and offer evidence-based treatment such as cognitive behavioral therapies with a multidisciplinary team, including a physical therapist and psychologist, to manage these psychological comorbidities and improve outcomes in patients with knee OA. While kinesiophobia was found to be associated with poorer QoL and physical activity, future studies including larger observational cohort studies should be conducted to determine causal and prognostic relationships between kinesiophobia and outcomes in knee OA. LEVEL OF EVIDENCE: Level III, prognostic study.