The aim of this study was to examine whether patients who received a multicondition collaborative care intervention for chronic illnesses and depression had greater improvement in self-care knowledge and efficacy, and whether greater knowledge and self-efficacy was positively associated with improved target outcomes. A randomized controlled trial with 214 patients with comorbid depression and poorly controlled diabetes and/or coronary heart disease tested a 12-month team-based intervention that combined self-management support and collaborative care management. At 6 and 12 month outcomes the intervention group showed significant improvements over the usual care group in confidence in ability to follow through with medical regimens important to managing their conditions and to maintain lifestyle changes even during times of stress. Improvements in self care-efficacy were significantly related to improvements in depression, and early improvements in confidence to maintain lifestyle changes even during times of stress explained part of the observed subsequent improvements in depression.