In this systematic review, the antimicrobial effect of ion-substituted calcium phosphate biomaterials was quantitatively assessed.The literature was systematically searched up to the 6th of December 2021. Study selection and data extraction was performed in duplo by two independent reviewers with a modified version of the OHAT tool for risk of bias assessment. Any differences were resolved by consensus or by a referee. A mixed effects model was used to investigate the relation between the degree of ionic substitution and bacterial reduction.Of 1016 identified studies, 108 were included in the analysis. The methodological quality of included studies ranged from 6 to 16 out of 18 (average 11.4). Selenite, copper, zinc, rubidium, gadolinium, silver and samarium had a clear antimicrobial effect, with a log reduction in bacteria count of 0.23, 1.8, 2.1, 3.6, 5.8, 7.4 and 10 per atomic% of substitution, respectively. There was considerable between-study variation, which could partially be explained by differences in material formulation, study quality and microbial strain. Future research should focus on clinically relevant scenariosin vitroand the translation toin vivoprevention of PJI.