This study analyzed the effects of a fluoride (F) varnish supplemented with sodium trimetaphosphate (TMP) on the remineralization of caries-like lesions in situ. Twelve subjects used palatal devices with demineralized enamel discs for 3 days, following a double-blind, crossover protocol. Test groups included placebo (no F or TMP), 5% NaF and 5% NaF/5% TMP varnishes. The percentage of surface hardness recovery (%SHR) and cross-sectional hardness (ΔKHN) were determined. Significant differences were observed among all varnishes regarding %SHR and ΔKHN. The highest %SHR and the lowest ΔKHN were seen for the 5% NaF/5% TMP varnish, followed by 5% NaF and placebo. The remineralizing effect of a 5% NaF varnish is significantly enhanced when associated with TMP. The reduction in the subsurface lesion area of enamel treated with the TMP-containing varnish implies that cavities would take longer to develop or might not develop at all depending on individual factors, resulting in lower net caries increments at individual and population levels.