Purpose: The purpose of this in vitro study was to compare caries resistance of sound human enamel following argon laser (AL) irradiation, as well as, combinations of topical fluoride foams and AL irradiation. Methods and Materials: Thirty extracted human teeth were sectioned into four buccal windows and assigned to one of the following treatment groups: (1) no treatment/control; (2) low fluence (11.5 J/cm2) AL irradiation for 10 seconds; (3) 1.23% APF foam for 4 minutes followed by low fluence AL irradiation; (4) 2.0% NaF foam for 4 minutes followed by low fluence AL irradiation. Caries-like lesions were created by submerging the teeth in ten Cate solution (pH 4.5). Following a 96-hour exposure period, 100 μm longitudinal sections were prepared for polarized light evaluation. Visilog 5.1.1. image analysis software was used to obtain quantitative lesion depths. The Scheffe F-test was used to compare the lesion depths for each of the four treatment groups. Results: Lesion depths were: 16.1 ± 6 μm for control; 13.7 ± 4 μm for AL irradiation alone; 12.1 ± 4.3 μm for 1.23% APF foam before AL irradiation; and 11.4 ± 5.9 μm for 2.0% NaF foam before AL irradiation. Significant difference (p < 0.05) was found between the control group and the 2.0% NaF foam before AL irradiation group. AL irradiation alone reduced lesion depth by 15% compared with the control lesion. When AL irradiation was combined with 1.23% APF foam treatment, lesion depth decreased by 25% compared with control lesions, and by 29% when combined with 2.0% NaF foam. Conclusion: Combining AL irradiation and 2.0% NaF foam treatment significantly enhances the resistance of sound enamel to an in vitro cariogenic challenge.