Purpose: Major depressive disorder (MDD) is highly prevalent in patients with a chronic physical condition, and this comorbidity has a negative influence on quality of life, health care costs, self-care, morbidity, and mortality. Research has shown that collaborative care (CC) may be a cost-effective treatment. However, its cost-effectiveness in this patient group has not yet been established. Therefore, the aim of this study was to evaluate the cost-utility of CC for the treatment of comorbid MDD in chronically ill patients in the outpatient general hospital setting. The study was conducted from a health care and societal perspective. Patients and methods: In this randomized controlled trial, 81 patients with moderate-to-severe MDD were included; 42 were randomly assigned to the CC group and 39 to the care as usual (CAU) group. We applied the TiC-P, short-form Health-Related Quality of Life questionnaire, and EuroQol EQ-5D 3 level version, measuring the use of health care, informal care, and household work, respectively, at baseline and at 3, 6, 9, and 12 months follow-up. Results: The mean annual direct medical costs in the CC group were €6,718 (95% confidence interval [CI]: 3,541 to 10,680) compared to €4,582 (95% CI: 2,782 to 6,740) in the CAU group. The average quality-adjusted life years (QALYs) gained were 0.07 higher in the CC group, indicating that CC is more costly but also more effective than CAU. From a societal perspective, the incremental cost-effectiveness ratio was €24,690/QALY. Conclusion: This first cost-utility analysis in chronically ill patients with comorbid MDD shows that CC may be a cost-effective treatment depending on willingness-to-pay levels. Nevertheless, the low utility scores emphasize the need for further research to improve the cost-effectiveness of CC in this highly prevalent and costly group of patients.