CONTEXT: Children with medical comorbidities are at greater risk for severe influenza and poorer clinical outcomes. Despite recommendations and funding, influenza vaccine coverage remains inadequate in these children. OBJECTIVE: We aimed to systematically review literature assessing interventions targeting influenza vaccine coverage in children with comorbidities and assess the impact on influenza vaccine coverage. DATA SOURCES: PubMed, Scopus, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Allied and Complementary Medicine Database, and Web of Science databases were searched. STUDY SELECTION: Interventions targeting influenza vaccine coverage in children with medical comorbidities. DATA EXTRACTION: Two reviewers independently screened articles, extracting studies' methods, interventions, settings, populations, and results. Four reviewers independently assessed risk of bias. RESULTS: From 961 screened articles, 35 met inclusion criteria. Published studies revealed that influenza vaccine coverage was significantly improved through vaccination reminders and education directed at either patients' parents or providers, as well as by vaccination-related clinic process changes. Interventions improved influenza vaccine coverage by an average 60%, but no significant differences between intervention types were detected. Significant bias and study heterogeneity were also identified, limiting confidence in this effect estimate. LIMITATIONS: A high risk of bias and overall low quality of evidence limited our capacity to assess intervention types and methods. CONCLUSIONS: Interventions were shown to consistently improve influenza vaccine coverage; however, no significant differences in coverage between different intervention types were observed. Future well-designed studies evaluating the effectiveness of different intervention are required to inform future optimal interventions.