Objective. To determine whether symptomatic (painful/problematic) joints pre-total knee replacement (TKR) surgery influence 1) pre-and 12-month post-TKR patient-reported outcomes (pain, physical function, and mood [fatigue, anxiety, and depression]) and 2) postsurgical pain and function mediated through mood. Methods. A total of 494 participants completed the patient-reported outcome measures pre-and 12-months post-TKR. Symptomatic (painful/problematic) joints affected by arthritis were indicated on a homunculus presurgery. Covariate data included age, sex, educational attainment, body mass index, and comorbidity. Pre-and postsurgical outcome scores were regressed on symptomatic joint sites and covariates using linear regression analyses; postsurgical scores additionally were regressed on presurgery scores. Path analyses examined whether the effects of symptomatic joint sites on postsurgical pain and function were mediated through mood. Results. The age range was 35-88 years (mean 65 years) and 65% were women. Forty-six percent reported >4 symptomatic joints (other than the surgical knee). Pre-and postsurgery, worse outcome scores were observed with increasing joint count. Adjusted for covariates, individuals reporting symptomatic ankles/feet/toes, neck, and spine/lower back had worse presurgery fatigue and anxiety. Adjusted for covariates and presurgery status, worse fatigue for the neck and spine/lower back and worse depression, pain, and function for the ankles/feet/toes and neck were observed postsurgery. The influence of symptomatic ankles/feet/toes on postsurgical pain and function was in part direct and partially mediated through depression. Full mediation was found for the neck through fatigue, anxiety, and depression, and for the spine/lower back through fatigue. Conclusion. Findings suggest that a comprehensive approach to osteoarthritis management/care is warranted, and identify important associations between symptomatic joints and mood that negatively impact post-TKR pain and physical function.