Background: Population mail-out bowel screening programs are a convenient, cost-effective and sensitive method of detecting colorectal cancer (CRC). Despite the increased survival rates associated with early detection of CRC, in many countries, 50% or more of eligible individuals do not participate in such programs. The current study systematically reviews interventions applied to increase fecal occult blood test (FOBT) kit return, specifically in population mail-out programs. Methods: Five electronic databases (PubMed, PsycINFO, Scopus, CINAHL, and ProQuest Dissertations and Theses) were searched for articles published before the 10th of March 2018. Studies were included if they reported the results of an intervention designed to increase the return rate of FOBT kits that had been mailed to individuals' homes. PRISMA systematic review reporting methods were applied and each study was assessed using Cochrane's Risk of Bias tool. Pooled effect sizes were calculated for each intervention type and the risk of bias was tested as a moderator for sensitivity analysis. Results: The review identified 53 interventions from 30 published studies from which nine distinct intervention strategy types emerged. Sensitivity analysis showed that the risk of bias marginally moderated the overall effect size. Pooled risk ratios and confidence intervals for each intervention type revealed that telephone contact RR = 1.23, 95% CI (1.08-1.40), GP endorsement RR = 1.19, 95% CI (1.10-1.29), simplified test procedures RR = 1.17, 95% CI (1.09-1.25), and advance notifications RR = 1.09, 95% CI (1.07-1.11) were effective intervention strategies with small to moderate effect sizes. Studies with a high risk of bias were removed and pooled effects remained relatively unchanged. Conclusions: Interventions that combine program-level changes incorporating the issue of advance notification and alternative screening tools with the involvement of primary health professionals through endorsement letters and telephone contact should lead to increases in kit return in mail-out CRC screening programs. Systematic review registration: This review is registered with PROSPERO; registration number CRD42017064652