OBJECTIVE: Patients accessing the chronic disease self-management programme (CDSMP) often report multiple long-term conditions (multimorbidity). Although multimorbidity often predicts poor outcomes, CDSMP effectiveness may be enhanced in multimorbidity via synergies between self-management for different conditions. This study assessed whether CDSMP benefits varied by patterns of multimorbidity. METHODS: The study was based on a secondary analysis of an RCT. Patients with long-term conditions (n=629) were randomised to CDSMP or wait-list and completed baseline and 6 month assessments. We identified four multimorbidity groups: (1) single physical condition; (2) multiple physical conditions; (3) single physical condition plus 'probable depression'; (4) multiple physical conditions plus 'probable depression'. RESULTS: Multimorbidity group significantly moderated the effect of CDSMP on vitality, health-related quality of life, and mental well-being, with the greatest benefit found for patients with multiple physical conditions plus 'probable depression'. CONCLUSION: The coexistence of depression and multiple physical conditions is associated with increased illness burden, but such patients benefit more from the CDSMP. The mechanisms underlying this effect are unclear, but it does not appear to be through self-management or self-efficacy. PRACTICE IMPLICATIONS: The presence of multimorbidity in combination with depression may be a useful criteria for referral to the CDSMP.