The objective of this study was to appraise the clinical evidence and its bias risk regarding the anticariogenic effect of xylitol in comparison with that of fluoride. Databases were searched for clinical trials up to 18 March 2011. Article inclusion criteria were as follows: caries-related primary outcomes were tested; xylitol was compared with topical fluoride in some form; two-arm (or more) clinical trial including test/control group(s); prospective study design. Article exclusion criteria were as follows: no computable data were reported; test and control groups were not followed up in the same way; chewing gum was the main form of clinical application in either group. Individual continuous datasets were extracted from accepted articles. Selection and performance/detection bias were assessed. Sensitivity analysis was used to investigate attrition bias risk. Egger’s regression and funnel plot was used to investigate publication bias risk. Twelve articles were included. Of these, six were accepted and six excluded, and 21 continuous datasets were extracted. Owing to the high clinical heterogeneity, no meta-analysis was performed. The addition of xylitol to existing fluoride regimes may be beneficial in the prevention of caries. However, all identified trials were limited by potential risk of selection, performance/detection and attrition bias. The funnel plot and Egger’s regression results (−2.80; 95% confidence interval −4.01, −1.58; P = 0.0001) indicated possible publication bias risk. External fluoride access may have confounded the measured anticariogenic effect of xylitol. The evidence found contains a high risk of bias and may be limited by confounder effects. Future high-quality randomised controlled trials are needed in order to provide conclusive evidence on this topic.