BACKGROUND: In 2004, a World Health Report on road safety called for enforcement of measures such as seatbelt use, effective at minimizing morbidity and mortality caused by road traffic accidents. However, injuries caused by seatbelt use have also been described. Over a decade after publication of the World Health Report on road safety, this study sought to investigate the relationship between seatbelt use and major injuries in belted compared to unbelted passengers. METHODS: Cohort studies published in English language from 2005 to 2018 were retrieved from seven databases. Critical appraisal of studies was carried out using the Scottish Intercollegiate Guidelines Network (SIGN) checklist. Pooled risk of major injuries was assessed using the random effects meta-analytic model. Heterogeneity was quantified using I-squared and Tau-squared statistics. Funnel plots and Egger's test were used to investigate publication bias. This review is registered in PROSPERO (CRD42015020309). RESULTS: Eleven studies, all carried out in developed countries were included. Overall, the risk of any major injury was significantly lower in belted passengers compared to unbelted passengers (RR 0.47; 95%CI, 0.29 to 0.80; I2 = 99.7; P = 0.000). When analysed by crash types, belt use significantly reduced the risk of any injury (RR 0.35; 95%CI, 0.24 to 0.52). Seatbelt use reduces the risk of facial injuries (RR = 0.56, 95% CI = 0.37 to 0.84), abdominal injuries (RR = 0.87; 95% CI = 0.78 to 0.98) and, spinal injuries (RR = 0.56, 95% CI = 0.37 to 0.84). However, we found no statistically significant difference in risk of head injuries (RR = 0.49; 95% CI = 0.22 to 1.08), neck injuries (RR = 0.69: 95%CI 0.07 to 6.44), thoracic injuries (RR 0.96, 95%CI, 0.74 to 1.24), upper limb injuries (RR = 1.05, 95%CI 0.83 to 1.34) and lower limb injuries (RR = 0.77, 95%CI 0.58 to 1.04) between belted and non-belted passengers. CONCLUSION: In sum, the risk of most major road traffic injuries is lower in seatbelt users. Findings were inconclusive regarding seatbelt use and susceptibility to thoracic, head and neck injuries during road traffic accidents. Awareness should be raised about the dangers of inadequate seatbelt use. Future research should aim to assess the effects of seatbelt use on major injuries by crash type.