We explored whether the effects of a telephone-based osteoarthritis (OA) self-management support intervention differed by race and health literacy. Participants included 515 veterans with hip and/or knee OA. Linear mixed models assessed differential effects of the intervention compared with health education (HE) and usual care (UC) on pain (Arthritis Impact Measurement Scales-2 [AIMS2] and Visual Analogue Scale), function (AIMS2 mobility and walking/bending), affect (AIMS2) and arthritis self-efficacy by: (i) race (white/non-white), (ii) health literacy (high/low) and (iii) race by health literacy. AIMS2 mobility improved more among non-whites than whites in the intervention compared with HE and UC (P = 0.02 and 0.008). AIMS2 pain improved more among participants with low than high literacy in the intervention compared with HE (P = 0.05). However, we found a differential effect of the intervention on AIMS2 pain compared with UC according to the combination of race and health literacy (P = 0.05); non-whites with low literacy in the intervention had the greatest improvement in pain. This telephone-based OA intervention may be particularly beneficial for patients with OA who are racial/ethnic minorities and have low health literacy. These results warrant further research designed specifically to assess whether this type of intervention can reduce OA disparities.