Evidence supporting the effectiveness of care management programs for complex patients has been inconclusive. However, past reviews have not focused on complexity primarily defined by multimorbidity and healthcare utilization. We conducted a systematic review of care management interventions targeting the following three patient groups: adults with two or more chronic medical conditions, adults with at least one chronic medical condition and concurrent depression, and adults identified based solely on high past or predicted healthcare utilization. Eligible studies were identified from PubMed, published between 06/01/2005 and 05/31/2015, and reported findings from a randomized intervention that tested a comprehensive, care management intervention. Identified interventions were grouped based on the three “complex” categories of interest (described above). Two investigators extracted data using a structured abstraction form and assessed RCT quality. We screened 989 article titles for eligibility from which 847 were excluded. After reviewing the remaining 142 abstracts, 83 articles were excluded. We reviewed the full-text of 59 full-text articles and identified 15 unique RCTs for the final analysis. Of these 15 studies, two focused on patients with two or more chronic medical conditions, seven on patients with at least one chronic medical condition and depression, and six on patients with high past or predicted healthcare utilization. Measured outcomes included utilization, chronic disease measures, and patient-reported outcomes. The seven studies targeting patients with at least one chronic medical condition and depression demonstrated significant improvement in depression symptoms (ranging from 9.2 to 48.7% improvement). Of the six studies that focused on high utilizers, two showed small reductions in utilization. The quality of the research methodology in most of the studies (12/15) was rated fair or poor. Interventions were more likely to be successful when patients were selected based on having at least one chronic medical condition and concurrent depression, and when patient-reported outcomes were assessed. Future research should focus on the role of mental health in complex care management, finding better methods for identifying patients who would benefit most from care management, and determining which intervention components are needed for which patients.