Objective: This randomized controlled trial tested a tailored, telephone-based physical activity coaching intervention for a predominantly African American group of women with severe obesity and mobility disability. Methods: We recruited 92 clinic patients from the University of Illinois at Chicago Medical Center referred by their physicians during 2004-2007 and randomized participants to one of three groups - awareness (informational brochure, no coaching), lower support (phone coaching only) and higher support (phone coaching plus monthly exercise support group) - to determine the efficacy of a tailored coaching intervention on key health outcomes, which included body weight and body mass index, blood pressure, cholesterol, physical activity (barriers and self-reported activity), movement and mobility, general health, and social support. Results: The higher support group had the greatest reduction in Body Mass Index (BMI) (7.4%) compared with a 0.2% and 1.6% increase in BMI for the lower support and awareness groups, respectively (p < .01). Both the higher and lower support groups had a greater increase in physical activity scores (39% and 30%, respectively) compared with a decline of 13% in the awareness group (p < .05). Conclusion: Providing phone-based coaching and monthly in-person exercise support group sessions appear to be an effective approach for reducing body weight and increasing physical activity among severely obese, disabled adults residing in difficult social environments. © 2009 The Institute For Cancer Prevention.