IMPORTANCE: The inclusion of digital therapeutics (eg, virtual reality [VR] systems) for the management of pain and anxiety associated with routine acutely painful medical procedures may have a substantial impact on treatment adherence and improve long-term health outcomes among young patients. OBJECTIVE: To determine whether a VR intervention decreases pain and anxiety among patients undergoing peripheral intravenous catheter (PIVC) placement compared with standard care in the pediatric setting. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted from April 12, 2017, to July 24, 2019, among 107 patients aged 10 to 21 years who were undergoing PIVC placement in 2 clinical settings (a radiology department and an infusion center) at an urban pediatric academic medical center in the US. Patients, caregivers, and clinicians completed pre-PIVC and post-PIVC placement questionnaires measuring patient pain, anxiety, and anxiety sensitivity; only participants with complete data from before and after PIVC placment were included in the analyses. INTERVENTIONS: Patients were randomized to receive standard care (simple distraction techniques [eg, music, coloring, singing, and talking] and the application of numbing cream) or a VR intervention using a balanced computer-generated randomization scheme stratified by sex. All patients who received the VR intervention were offered concurrent standard care; however, VR plus standard care was not specifically examined. MAIN OUTCOMES AND MEASURES: Primary outcomes were patient pain (measured by the Faces Pain Scale-Revised) and anxiety (measured by a visual analogue scale) reported by the patient, caregiver, and clinician after PIVC placement. Outcomes were analyzed using generalized linear modeling with backward stepwise selection for final model building. RESULTS: A total of 107 patients (median age, 14.7 years [interquartile range, 12.8-16.9 years]; 63 male participants [58.9%]) completed the clinical trial; 54 patients received standard care, and 53 patients also received the VR intervention. Patients who received the VR intervention compared with standard care had significantly lower mean post-PIVC anxiety scores when patient-reported (1.85 points [95% CI, 1.28-2.41 points] vs 3.14 points [95% CI, 2.59-3.68 points]; P < .001) and clinician-reported (2.04 points [95% CI, 1.37-2.71 points] vs 3.34 points [95% CI, 2.69-3.99 points]; P = .002). Patients in the VR group vs the standard care group also had significantly lower mean post-PIVC pain scores when patient-reported (1.34 points [95% CI, 0.63-2.05 points] vs 2.54 points [95% CI, 1.78-3.30 points]; P = .002), caregiver-reported (1.87 points [95% CI, 0.99-2.76 points] vs 3.01 points [95% CI. 1.98-4.03 points]; P = .04), and clinician-reported (2.05 points [95% CI, 1.47-2.63 points] vs 3.59 points [95% CI, 2.97-4.22 points]; P < .001). Aside from lower levels of baseline pain and anxiety, no demographic variables among patients in the VR group were associated with lower levels of post-PIVC pain and anxiety. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, patients undergoing PIVC placement who received a VR intervention experienced significantly less anxiety and pain compared with those who received standard care. The use of patient, caregiver, and clinician data provided a variety of subjective information, as well as observable and objective data regarding perceived pain and anxiety beyond patient reporting alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: CHLA-15-00549.