The use of fluoride gel applied in a custom tray once daily has become standard for patients who have xerostomia after undergoing radiation therapy. Compliance may be poor as a result of the inconvenient method of application and because many patients with head and neck cancer have poor health behaviors. Our aim was to investigate the effect of compliance with fluoride gel application on caries and caries risk. Patients were prescribed neutral sodium fluoride gel (5000 ppm) before undergoing radiotherapy Fifty-two patients were willing to visit the dental clinic for dental examination, measurement of saliva, and quantitative culture of Streptococcus mutans and lactobacillus species. Before radiotherapy was performed, decayed, missing, and filled surfaces data were recorded for all patients in the study. Of these patients, 27 used fluoride gel once daily, as directed. Radiation dose, number of fractions, and duration of radiation had a significant inverse effect on postradiotherapy whole resting saliva (p = 0.04, p = 0.01, and p = 0.01) and on whole stimulated saliva (p = 0.02, p < 0.01, and p < 0.01). Patients with a subjective feeling of dry mouth had significantly less saliva production at rest (p = 0.01) and on stimulation (p = 0.01). A trend toward reduction of S. mutans counts was seen in those patients who used their fluoride gel regularly (p = 0.057). High lactobacilli counts were found in the patients with high and low compliance with fluoride gel use. Differences in the mean caries incidence between those who reported compliance with daily fluoride application and those who did not comply were not found significant because of the large SD in the patient groups, although differences in the mean for these groups were seen. The lack of a statistically significant difference may be due to the multiple factors associated with caries. Therefore patient care must be individualized, and patients must be assessed at regular intervals to determine the caries risk and caries activity to provide guidance for maintenance of the dentition.