– There is limited evidence from clinical trials on the dose response of sodium fluoride dentifrices at concentrations above 1100 ppm fluoride ion, with respect to caries efficacy. This randomized, double‐blind study examined the anti‐caries effectiveness of sodium fluoride dentifrices containing 1700 ppm, 2200 ppm and 2800 ppm fluoride ion relative to an 1100 ppm fluoride ion control. A population of 5439 elementary schoolchildren, aged 6–15 years, was recruited from an urban central Ohio area with a low fluoride content water supply (<0.3 ppm). Subjects were examined by visual‐tactile and radiographic examination at baseline and after 1, 2, and 3 years of using the sodium fluoride dentifrices. Subjects were stratified according to gender, age and baseline DMFS scores derived from the visual‐tactile baseline examination and randomly assigned to one of four treatment groups: 0.243% sodium fluoride (1100 ppm fluoride ion), 0.376% sodium fluoride (1700 ppm fluoride ion), 0.486% sodium fluoride (2200 ppm fluoride ion), and 0.619% sodium fluoride (2800 ppm fluoride ion). All products were formulated with the same fluoride compatible silica abrasive. Results after 1 year provided evidence of a positive sodium fluoride dose response. Compared to the 1100 ppm fluoride treatment group, the 1700 ppm fluoride treatment group had an 11.0% reduction in DMFS that was not statistically significant, while the 2200 ppm and 2800 ppm fluoride treatment groups showed statistically significant (P<0.05) reductions of 18.6% and 20.4%, respectively. The reductions in caries delivered by the higher fluoride dentifrices were present across all tooth surface types, but were most pronounced for occlusal surfaces. Results at years 2 and 3 were confounded by a concurrent fluoride rinse program, which involved portions of the study population. While the trends for the higher fluoride dentifrices observed at year 1 remained at years 2 and 3, the difference observed between treatments were substantially less and failed to reach statistical significance (P<0.05). Collectively, the data demonstrate that the 2200 ppm and the 2800 ppm fluoride treatments delivered statistically significantly greater caries efficacy than the 1100 ppm fluoride treatment. This large‐scale clinical trial provides evidence of a positive statistically significant dose relationship between dental caries and sodium fluoride in a dentifrice at levels above 1100 ppm fluoride at year 1.