PURPOSE: To test the hypothesis that a long-term structured physical activity program is more effective than a health education program in reducing the risk and progression of self-reported disability in basic activities of daily living (ADL’s), instrumental ADL’s (IADL’s) and mobility disability (e.g. bathing, doing light housework, walking a block). METHODS: The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, single-blinded randomized trial of 1,635 sedentary men and women aged 70-89 years, who had functional limitations, defined as a score < 10 on the Short Physical Performance Battery. Participants were randomized to a structured moderate intensity physical activity (PA) program (n=818) that included including aerobic, resistance and flexibility exercises or to a health education (HE) program (n=817). Outcomes were assessed with semi-annual interviews that asked about the degree of difficulty and receiving help during the past month in executing ADLs, IADLs and mobility activities. The first occurrence of receiving assistance or being unable to perform ≥ 1 ADLs served as the primary outcome. Secondary outcomes included the first occurrence of having a lot of difficulty or unable to do ≥ 1 activities in each of the three functional domains. Severe disability was defined as reporting difficulty or being unable to perform ≥ 3 activities in each of the three domains. RESULTS: Over an average follow-up of 2.56 years, the cumulative incidence of receiving assistance or being unable to perform ≥ 1 ADLs was 15.2% (120/787) of PA and 15.1% (120/793) of HE participants (HR=1.0, 95%CI=0.78-0.1.3, p=0.97). Similar results were found with incident IADL (HR=1.0, 95%CI=0.79-1.3, p=0.97) and mobility disability (HR=0.97, 95%CI=0.82-1.15, p=0.70). Severe mobility disability (HR=0.78, 95%CI=0.64-0.96, p=0.02), but not severe ADL (p=0.69) or IADL (p=0.52) disability was reduced with PA. CONCLUSIONS: A structured moderate intensity physical activity program, compared with a health education program, showed no effect on self-reported ADL or IADL disability. Self-report of severe mobility disability was reduced over 2.6 years of follow-up. These results support the effectiveness of a physical activity intervention designed to reduce severe mobility disability, but additional interventions are needed to prevent ADL and IADL disability in older adults with functional limitations.