Objective. To determine the association of the underlying diagnosis with limitation in activities of daily living (ADL) and pain in patients undergoing primary total knee arthroplasty (TKA). Methods. Prospectively collected data from the Mayo Clinic Total Joint Registry were used to assess the association of diagnosis with moderate-severe limitation in ADL and moderate-severe pain at 2 and 5 years after primary TKA, using multivariable-adjusted logistic regression analyses. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs). Results. There were 7,139 primary TKAs at 2 years and 4,234 at 5 years. In multivariable-adjusted analyses, compared with rheumatoid arthritis (RA)/inflammatory arthritis, osteoarthritis (OA) was associated with significantly lower moderate-severe ADL limitation at 2 years (OR 0.5 [95% CI 0.3-0.8]) (P = 0.004) and at 5 years (OR 0.5 [95% CI 0.3-0.9]) (P = 0.02). There was no significant association of diagnosis of OA with moderate-severe pain at 2 years (OR 1.2 [95% CI 0.5-2.7]) (P = 0.68) or at 5 years (OR 1.0 [95% CI 0.3-3.7]) (P = 1.0). Conclusion. We found that patients with OA who underwent primary TKA had better ADL outcomes compared to patients with RA/inflammatory arthritis at 2 and 5 years. On the other hand, the pain outcomes after primary TKA did not differ in OA versus RA. This suggests a discordant effect of underlying diagnosis on pain and function outcomes after TKA. These novel findings can be used to better inform both patients and surgeons about expected pain and function outcomes after primary TKA. © 2013 by the American College of Rheumatology.