This investigation evaluated the efficacy of two bicarbonate-containing dentifrices (one with fluoride and one without) against one placebo dentifrice (containing neither fluoride nor bicarbonate) in vivo in a panel of human volunteers to determine whether or not sodium bicarbonate would affect salivary mutans streptococci and lactobacilli. Ten caries-inactive adults were divided randomly into three groups, each of which was exposed to all three dentifrices, in a crossover manner, during three 4-week test periods. Saliva samples were taken at 1-week intervals. Samples were stored on ice, and microbiological analyses were conducted. The statistical analyses showed that, over a 4-week period, there was a statistically significant (p < 0.05) reduction in numbers of mutans streptococci with the two bicarbonate dentifrices as compared with the placebo dentifrice. Although not statistically significant, a similar trend was observed with lactobacilli. Longer-term, large-scale studies need to be conducted to investigate the possible mechanisms of action of sodium bicarbonate on these organisms and to relate the results to possible cariostatic effects in humans.