Background and aims: Physical exercise is associated with a lower risk of disability. The impact of comorbidity on the benefits from physical exercise has not been clearly investigated. Elders with comorbidity may benefit from physical exercise to preserve physical function. Methods: Data are from 435 participants with knee osteoarthritis aged ≥60 years enrolled in the Fitness and Arthritis in Seniors Trial (FAST), who were randomly assigned to 18-month health educational (HE), weight training (WT), or aerobic exercise (AE) interventions. Comorbidity was defined as the presence of osteoarthritis and ≥2 clinical conditions. Percent changes in the 6-minute walk test, self-reported disability and knee pain from baseline to 3-, 9-, and 18-month follow-up visits were analyzed according to comorbidity, using analysis of variance. Significances were adjusted using the Bonferroni method. Results: Mean age of the sample was 68.7 years. In participants with comorbidity (n=197), those in the AE intervention showed significant improvement in walking speed, compared to WT and HE groups, since the beginning of follow-up. Subjects with comorbidity in AE and WT groups showed improvement of the disability score at the 3-month follow-up visit compared to those in the HE group. This improvement was maintained at the end of the follow-up by the only AE group compared to the HE one (p=0.06). In participants with comorbidity, the pain score was improved by the AE intervention. Conclusions: AE and WT interventions improve physical function in individuals with comorbidity. AE improves physical function and knee pain independently of the presence of comorbidity.