Objective. To evaluate whether osteoarthritis (OA) pain determines depressed mood, taking into consideration fatigue and disability and controlling for other factors. Methods. In a community cohort with hip/knee OA, telephone interviews assessed OA pain and disability (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]), fatigue (Multidimensional Fatigue Symptom Inventory), depressed mood (Center for Epidemiologic Studies Depression Scale), and covariates (demographics, self-rated health, comorbidity, pain coping, pain catastrophizing, and social support) at 3 time points over 2 years. Drawing on previous research, a path model was developed to test the interrelationships among the key concepts (pain, depression, fatigue, disability) over time, controlling for covariates. Results. The baseline mean age was 75.4 years; 78.5% of the subjects were women, 37.2% were living alone, and 15.5% had >3 comorbid conditions. WOMAC scores indicated moderate OA symptoms and disability. From the final model with 529 subjects, adjusting for covariates, we found that current OA pain strongly predicted future fatigue and disability (both short and long term), that fatigue and disability in turn predicted future depressed mood, that depressed mood and fatigue were interrelated such that depressed mood exacerbated fatigue and vice versa, and that fatigue and disability, but not depressed mood, led to worsening of OA pain. Conclusion. Controlling for other factors, OA pain determined subsequent depressed mood through its effect on fatigue and disability. These effects led to worsening of pain and disability over time. These results support the need for improved pain management in OA to prevent or attenuate the downstream effects of pain on disability and mood.