OBJECTIVE A randomized, investigator-blind, five-treatment, crossover, non-inferiority study was conducted to investigate the effect of the addition of calcium sodium phosphosilicate (CSPS), an agent known to relieve dentin hypersensitivity, to a sodium monofluorophosphate (SMFP)-containing dentifrice on the enamel remineralization potential of fluoride (F), as assessed by percentage surface microhardness recovery (%SMHR) and enamel fluoride uptake (EFU) using a standard in situ caries model. METHODS Seventy-seven subjects wearing bilateral mandibular partial dentures holding partially demineralized bovine enamel specimens 24 hours/day brushed their teeth with their assigned randomized dentifrice containing either 1500 or 0 ppm F with 5% CSPS or 1500, 500, or 0 ppm F with 0% CSPS twice daily for 21 days. The success criterion was to observe a difference in % SMHR between dentifrices containing 1500 ppm F of six units or less in the upper bound of the two-sided 95% confidence interval (CI). RESULTS Following 21 days of treatment, the upper bound CI of the %SMHR difference between the dentifrices containing 1500 ppm F was 1.66, thus within the non-inferiority limit. No statistically significant differences for %SMHR (p = 0.2601) and EFU (p = 0.2984) were noted between these two dentifrices. CONCLUSIONS The present in situ caries study provides evidence demonstrating that the addition of the calcium-containing compound CSPS to a 1500 ppm F dentifrice does not interfere with the ability of fluoride to remineralize surface-softened enamel; i.e., CSPS neither impairs nor improves the potential cariostatic value of SMFP dentifrice.