Purpose: We sought to develop and evaluate the efficacy of an innovative, theory-driven, group stress self-management intervention designed to ameliorate stress and promote health among women with physical disabilities such as spinal cord injury, multiple sclerosis, and arthritis. Methods: We recruited a voluntary sample of 78 community-living women with disabilities who were randomly assigned to either the group stress management intervention or the wait-listed control group, and we used a within- and between-groups pretest/posttest design with a 3-month follow-up. Results: Group differences in changes over time on measures of perceived stress and mental health offer support for the efficacy of the intervention. At the 3-month follow-up assessment, the intervention group also showed greater improvement on measures of pain and role limitations owing to physical health when compared the wait-listed control group. Perceived stress was supported as a mediator of the effect of the intervention on mental health. We found support for social connectedness and self-efficacy as mediators of the relation between the intervention and perceived stress; however, there was relatively weak evidence for differential change over time in those proposed mediators. Conclusion: This study provides the first of its kind, that is, an evaluation of the efficacy of a stress self-management intervention designed specifically for women with physical disabilities. The results are consistent with a model in which the stress management intervention enhances self-efficacy and social connectedness, which leads to reduced stress, which then contributes to improved mental health.