OBJECTIVE: Pain persistence following knee replacement (KR) occurs in ∼20-30% of patients. Although several studies have identified preoperative risk factors for persistent post-KR pain, few have focused on post-KR contributing factors. We sought to determine whether altered nociceptive signaling and other peripheral nociceptive drivers present post-operatively contribute to post-KR pain. DESIGN: We included participants from the Multicenter Osteoarthritis Study who were evaluated ∼12 months after KR. We evaluated the relation of measures of pain sensitivity [pressure pain threshold (PPT), temporal summation (TS), and conditioned pain modulation (CPM)] and the number of painful body sites to post-KR WOMAC knee pain, and of the number of painful sites to altered nociceptive signaling using linear or logistic regression models, as appropriate. RESULTS: 171 participants (mean age 69 years, 62% female) were included. TS was associated with worse WOMAC pain post-KR (β ​= ​0.77 95% CI:0.19-1.35) and reduced odds of achieving patient acceptable symptom state (aOR ​= ​0.54 95%CI:0.34-0.88). Inefficient CPM was also associated with worse WOMAC pain post-KR (β ​= ​1.43 95% CI:0.15-2.71). In contrast, PPT was not associated with these outcomes. The number of painful body sites present post-KR was associated with TS (β ​= ​0.05, 95% CI:0.01, 0.05). CONCLUSIONS: Post-KR presence of central sensitization and inefficient descending pain modulation was associated with post-KR pain. We also noted that presence of other painful body sites contributes to altered nociceptive signaling, and this may thus also contribute to the experience of knee pain post-KR. Our findings provide novel insights into central pain mechanisms and other peripheral pain sources contributing to post-KR persistent knee pain.