Objective: Collaborative care (CC) improves depressive symptoms in people with comorbid depressive disorder in chronic medical conditions, but its effect on physical symptoms has not yet systematically been reviewed. This study aims to do so., Methods: Systematic review and meta-analysis was conducted using PubMed, the Cochrane Library, and the European and US Clinical Trial Registers. Eligible studies included randomized controlled trials (RCTs) of CC compared to care as usual (CAU), in primary care and general hospital setting, reporting on physical and depressive symptoms as outcomes. Overall treatment effects were estimated for illness burden, physical outcomes and depression, respectively., Results: Twenty RCTs were included, with N=4774 patients. The overall effect size of CC versus CAU for illness burden was OR 1.64 (95%CI 1.47;1.83), d=0.27 (95%CI 0.21;0.33). Best physical outcomes in CC were found for hypertension with comorbiddepression. Overall, depression outcomes were better for CC than for CAU. Moderator analyses did not yield statistically significant differences., Conclusions: CC is more effective than CAU in terms of illness burden, physical outcomes and depression, in patients with comorbid depression in chronic medical conditions. More research covering multiple medical conditions is needed., Protocol Registration Number: The protocol for this systematic review and meta-analysis has been registered at the International Prospective Register of Systematic Reviews (PROSPERO) on February 19th 2016: http://www.crd.york.ac.uk/PROSPERO/DisplayPDF.php?ID=CRD42016035553., (Copyright © 2017 Elsevier Inc. All rights reserved.)