Objective: This in vivo pilot study investigated the role of argon laser irradiation and combined fluoride and argon laser treatment in accelerated natural caries development in sound enamel surfaces beneath plaque-retentive orthodontic bands. Method and materials: Five patients (3 female, 2 male, ages 19 to 28 years) requiring tooth extraction prior to orthodontic treatment, participated in the study. Buccal surfaces were treated with either: (1) argon laser (250 mW for 10 seconds, ARGO-MOD); (2) topical fluoride (0.5% fluoride ion, Thera-Flur-N) followed by argon lasing; or (3) no treatment (control). Orthodontic bands with plaque-retentive slots on buccal surfaces were placed on the teeth slated for extraction (n = 14). Following a minimum of 5 weeks of intraoral exposure, the teeth were extracted for laboratory analysis. The teeth underwent serial longitudinal sectioning (12 sections per tooth). The sections were imbibed in water, and lesion depths were determined with each section, using polarized light microscopy. Comparisons were made among treatment groups (analysis of variance, Duncan's multiple range test for paired samples). Results: Mean lesion depths were: 261 ± 24 µm for the no treatment control group (n = 84 sections); 147 ± 18 µm for the argon laser group (n = 24 sections); and 99 ± 12 µm for the fluoride and argon laser group (n = 60 sections). Both the argon laser (44%) and the fluoride and argon laser groups (62%) had significant lesion depth reductions compared to controls. The addition of fluoride treatment prior to argon lasing resulted in a 32% reduction in lesion depth compared to argon laser treatment alone. Conclusions: Within this clinical pilot study, in vivo natural caries formation was affected significantly by a single exposure to low fluence argon laser irradiation. Topical fluoride treatment in combination with argon lasing provided an even greater degree of resistance against in vivo enamel caries development. A simple technique for reducing the caries susceptibility of enamel may be a clinical reality.