Background: Drug therapy problems, adverse drug events (ADEs), and symptom burden are high among adults with disabilities. Objective: To compare the effects of a modified medication therapy management (MTM) program within a self-efficacy workshop versus the workshop alone or usual care on symptom burden among adults with activity limitations. Methods: Three-group randomized controlled trial among adults (age 40 and older) with self-reported activity limitations in community practice. Interventions: 8 weekly Living Well With a Disability (LWD) 2-hour workshop sessions with and without a collaborative medication management (CMM) module. Primary outcome: mean number of moderate to very severe symptoms from a list of 11 physical and mental symptoms. Process measures: changes in medication regimens and self-reported ADEs. Analysis: general linear mixed models (continuous outcomes) and generalized estimating equations (categorical outcomes). Results: Participants had high symptom burden, low physical health, and took many medications. There was a significant increase in ADE reporting in the LWD + CMM group relative to the other 2 groups (Study group × Time P = .014), and there were significantly more changes in medication regimens in the LWD + CMM group (P = .013 LWD only vs LWD + CMM). The oldest third of participants had significantly fewer mean symptoms but received more intense CMM. There was no difference between the LWD-only, LWD + CMM, and usual care groups in symptom burden over time. Conclusion: Pharmacist MTM practices and MTM guidelines may need to be modified to affect symptom burden in a population with physical activity limitations.