Chlorhexidine (CHX) is probably the most widely used and the most potent chemical plaque inhibitory agent, whereas fluoride (F−) is the only truly accepted anticaries agent available at present. As they have discrete mechanisms of action, a combination effect of these agents on human dental caries may exist. The inhibitory effect of CHX on the formation of, and acid production in, plaque may reduce a relatively extreme cariogenic challenge sufficiently for it to be overcome by the local F− concentrations achieved by brushing or rinses. The aim of this study was to evaluate the possible caries inhibitory effect of combining 2.2 mM CHX mouthrinses used twice daily with daily 11.9 mM NaF rinses in an in vivo human caries model using plaque‐retaining bands on premolars scheduled for extraction. Nine subjects (a total of 28 teeth) were fitted with the bands for 4 wk. Saliva and plaque samples were collected before and after the study period for bacterial cultures, and the tooth surfaces were analyzed by microradiography after careful tooth extractions. The combination of CHX and F− rinses resulted in enamel mineral loss only slightly higher than that observed in “sound” enamel and clearly less than with F− rinses alone. Both total plaque bacteria and Streptococcus mutans were reduced by CHX rinses, confirming the discrete mechanisms of action.