Objective. To evaluate the prevalence and determinants of clinically important fatigue before and up to 12 months after total knee replacement (TKR) surgery. Methods. This study was a secondary analysis of a prospective cohort study conducted among 422 patients (ages 4574 years) undergoing primary TKR for osteoarthritis (OA) who participated in the Maximum Recovery After Knee Replacement randomized clinical trial. Assessments were carried out before, and at 6 weeks, 6 months, and 12 months after surgery. Self-reported fatigue was assessed on a 10-cm visual analog scale. Patients also completed a number of questionnaires evaluating knee pain, activity limitations, psychological well-being, comorbidity, and physical activity. Linear regression analyses were conducted to explore 6- and 12-month cross-sectional and longitudinal associations with self-reported fatigue. Results. Clinically important fatigue (>= 6.7 of 10) was reported by 145 patients (34%) before surgery, decreasing to 14%, 12%, and 8% at 6 weeks, 6 months, and 12 months after surgery, respectively. In multivariate analyses, muscle strength was strongly associated with fatigue at 6 months, and knee pain, activity limitations, number of comorbidities, and lack of energy were strongly associated with fatigue at both 6 and 12 months after TKR surgery. Female sex, number of comorbidities, depression, and fatigue were all early predictors of fatigue 12 months after TKR. Conclusion. Among patients undergoing TKR for OA, clinically important fatigue is considerably prevalent both before and for at least 6 months after surgery. Identifying and addressing early predictors of ongoing fatigue has the potential to improve the quality of life following TKR surgery.