This prospective observational study evaluated preoperative predictors of CRPS outcomes 6 months following total knee arthroplasty (TKA). Participants were n=110 osteoarthritis patients (64.5% female) undergoing unilateral TKA with no prior CRPS history. Domains of negative affect (depression, anxiety, catastrophizing), pain (intensity, widespread pain, temporal summation of pain [TSP]), pain interference, sleep disturbance, and proinflammatory status (tumor necrosis factor-alpha [TNF-a]) were assessed preoperatively. CRPS outcomes at 6 week and 6 month follow-up included the continuous CRPS Severity Score (CSS) and dichotomous CRPS diagnoses (2012 IASP criteria). At 6 months, 12.7% of participants met CRPS criteria, exhibiting a "warm CRPS" phenotype. Six week CSS scores were predicted by greater preoperative depression, anxiety, catastrophizing, TSP, pain intensity, sleep disturbance, and TNF-a (p's<.05). Provisional CRPS diagnosis at 6 weeks was predicted by higher preoperative TSP, sleep disturbance, and TNF-a (p's<.05). CSS scores at 6 months were predicted by more widespread and intense preoperative pain, and higher preoperative TSP, pain interference, and TNF-a (p's<.01). CRPS diagnosis at 6 months was predicted only by more widespread and intense pain preoperatively (p's<.05). Risk for CRPS following TKA appears to involve preoperative central sensitization and inflammatory mechanisms. Preoperative negative affect is unlikely to directly influence long-term CRPS risk. PERSPECTIVE: : This article identifies preoperative predictors of CRPS features at 6 months following total knee arthroplasty, including more widespread pain and higher pain intensity, temporal summation of pain, pain interference, and tumor necrosis factor-alpha levels. Findings suggest the importance of central sensitization and inflammatory mechanisms in CRPS risk following tissue trauma.