Objective. This systematic review with meta-analyses sought to answer the following question: “Does CPP-ACP [casein phosphopeptide-amorphous calcium phosphate], when introduced into the oral environment, provide any caries-preventive benefit superior to that of any other intervention or placebo?” Material and methods. Seven electronic databases were searched for trials relevant to the review question. Twelve articles were accepted after application of inclusion and exclusion criteria. Results. Of the accepted articles, five in situ randomized control trials (RCT) could be pooled for meta-analyses. During the short-term (7-21 days) in situ trials, participants wore appliances containing enamel slabs that were analyzed in the laboratory after exposure to CPP-ACP. The pooled in situ results showed a weighted mean difference (WMD) of the percentage remineralization scores in favor of chewing gum with 18.8 mg CPP-ACP as compared to chewing gum without CPP-ACP (WMD -8.01; 95% CI: -10.54 to -5.48; p = 0.00001), as well as compared to no intervention (WMD -13.56; 95% CI: -16.49 to -10.62; p = 0.00001). A significant higher remineralization effect was also observed after exposure to 10.0 mg CPP-ACP (-7.75; 95% CI: -9.84 to -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). Conclusion. Within the limitations of this systematic review with meta-analysis, the results of the clinical in situ trials indicate a short-term remineralization effect of CPP-ACP. Additionally, the promising in vivo RCT results suggest a caries-preventing effect for long-term clinical CPP-ACP use. Further randomized control trials are needed in order to confirm these initial results in vivo.