Patients with sickle cell disease (SCD) experience a disproportionately high use of health care resources. Several studies have examined depression and other negative mood states as risk factors for increased health care utilization; however, there have been no systematic reviews examining and summarizing this evidence in SCD. The aim of this systematic review, therefore, was to determine whether depression or depressive symptoms are associated with health care utilization among children and adults with SCD. We followed a quantitative systematic review protocol based on the Preferred Reporting Items for Systematic Reviews and Meta- Analyses guidelines and performed a literature search of records from January 1980 to April 2014 using six databases. Empirical studies were eligible if the sample was primarily composed of patients with SCD and included data on depression, mood disorder diagnosis or depressive symptoms and health care utilization. We included 12 studies involving 54 036 unique participants. The prevalence estimates for depression ranged from 2–57%. Seven studies found a significant, or marginally significant, association between depression and utilization while five did not. Patients reporting depression had an estimated 2·8 times greater relative risk of being a high utilizer, and 2·9 versus 1·8 hospitalizations per year on average compared to patients without depression. Overall, depressive symptoms are common in SCD and may increase risk for poor outcomes including health care utilization. The available studies on depression in SCD, however, are limited by small sample sizes, retrospective designs or short follow-up. This systematic review found a modest association between depression and health care utilization in SCD.