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Background Collaborative care can effectively support the treatment of depression in people with multiple long-term physical conditions or mental-physical multimorbidity, but long term benefits and costs are unknown. AimsTo explore the long-term effectiveness and cost-effectiveness of collaborative care in people with mental-physical multimorbidity.MethodA cluster randomised trial of 36 general practices in England compared collaborative care with usual care (standard management by primary care staff) for people with depression and comorbid diabetes and/or coronary heart disease. Collaborative care included up to eight sessions of low-intensity psychological therapy with lifestyle/disease management advice (integrated physical and mental health care). Depression symptoms were measured using the symptom checklist-13 depression scale (SCL-D13) 24 months after baseline. The EQ-5D-5L was used to capture health status and calculate quality adjusted life years (QALYs) for the economic evaluation from the perspective of the National Health Service (NHS) in England.Results191 participants were allocated to collaborative care and 196 to usual care. At 24-months the mean SCL-D13 score was 0.27 (95% CI -0.48, -0.06) lower in participants in the collaborative care arm. Collaborative care was also associated with a QALY gain of 0.14 (95% CI 0.06, 0.21); the cost per additional QALY gained was £13,069. There is a 75% probability that collaborative care is cost-effective at a threshold of £20,000/QALY.ConclusionsIntegrated collaborative care effectively reduces depression over the long term and can improve physical functioning. Collaborative care is potentially cost-effective over the long-term at internationally accepted willingness to pay thresholds.