To find studies to include in the review, searches were made using Biomed Central, Cochrane Oral Health Reviews, Cochrane Library, the Directory of Open Access Journals, PubMed, Science Direct and the Research Findings Electronic Register.English language clinical trials [randomised clinical trials (RCT) or quasi-RCT; in situ or in vivo] or systematic reviews (with or without meta-analysis) of published trials were selected that reported on the efficacy of phosphopeptide-amorphous calcium phosphate (CPP-ACP) using any mode of delivery. Studies were reviewed and their quality assessed independently.Data was extracted by two reviewers independently. Trials that were considered clinically and methodologically homogenous and that reported on similar outcomes were pooled for meta-analyses.Twelve articles were included of which five in-situ RCT could be pooled for meta-analyses. The pooled in-situ results showed a weighted mean difference (WMD) of the percentage remineralisation scores in favour of chewing gum with 18.8 mg CPP-ACP, compared with chewing gum without CPP-ACP of -8.01 [95% confidence interval (CI), -10.54- -5.48; P 0.00001], and compared with no intervention of -13.56 (95% CI, -16.49- -10.62; P 0.00001). A significantly higher remineralisation effect was also observed after exposure to 10.0 mg CPP-ACP (WMD, -7.75; 95% CI, -9.84- -5.66; P 0.00001). One long-term in vivo RCT (24 months) with a large sample size (N = 2720) found that the odds of a tooth surface's progressing to caries was 18% less in subjects who chewed sugar-free gum containing 54 mg CPP-ACP than in control subjects who chewed gum without CPP-ACP (P 0.03).Within the limitations of this systematic review with meta-analysis, the results of the clinical in-situ trials indicate a short-term remineralisation effect of CPP-ACP. Additionally, the promising in-vivo RCT results suggest a caries-preventing effect for long-term clinical CPP-ACP use. Further RCT are needed in order to confirm these initial results in vivo.