Whether sunscreen use affects melanoma risk has been widely studied with contradictory results. To answer this question we performed a systematic review of all published studies, accounting for sources of heterogeneity and bias. We searched for original articles investigating the sunscreen-melanoma association in humans to 28.02.2018. We then used random-effects meta-analysis to combine estimates of the association, stratified by study design. Stratified meta-analysis and meta-regression were used to identify sources of heterogeneity. We included 21'069 melanoma cases from 28 studies published 1979-2018: 23 case-control (11 hospital-based, 12 population-based), 1 ecological, 3 cohort and 1 randomized controlled trial (RCT). There was marked heterogeneity across study designs and among case-control studies but adjustment for confounding by sun exposure, sunburns and phenotype systematically moved estimates towards decreased melanoma risk amongst sunscreen users. Ever- vs. never-use of sunscreen was inversely associated with melanoma in hospital-based case-control studies (adjusted odds ratio (OR)=0.57, 95%confidence interval (CI) 0.37-0.87, pheterogeneity