This study evaluated the effectiveness of the evidence-based, EnhanceFitness (EF) physical activity (PA) intervention in improving arthritis symptoms, physical and mental function, and PA in adults with arthritis. This was a community-based, randomized, controlled effectiveness trial that switched to a nonrandomized controlled trial. Participants were sedentary/low-active adults, aged ≥18 years, with self-reported physician-diagnosed arthritis, who were assigned to an immediate or delayed group (12-week, wait-list control group). Classes were held thrice weekly for 12 weeks at 17 community sites in 4 urban and 5 rural West Virginia counties. Data were collected at baseline, 12 weeks, and 24 weeks. The RE-AIM Framework evaluated EF's: (1) reach (enrollment); (2) effectiveness (outcomes); (3) adoption (proportion of sites/instructors that delivered EF); (4) implementation (attendance, fidelity, adverse events, and satisfaction); and (5) maintenance (EF continuation). Outcomes were analyzed using linear mixed-effects regression. There were 323 adults with a mean age of 68.3 years (range 27-95). Reach was 74%; site and instructor adoption rates were 100% and 55%, respectively; attendance (1.8 sessions per week) and fidelity were good; injury rate was low (3.8%); participants were highly satisfied and experienced improvements in arthritis symptoms and physical function; and 27% of instructors and 18% of sites continued EF. EnhanceFitness was safe and effective in improving arthritis symptoms and physical function in sedentary/low-active adults with arthritis, across the adult age spectrum, under real-world conditions, in both urban and rural communities.Clinical Trial Registration: NCT00526201.