Previous studies have demonstrated modifications in tooth structure after laser irradiation. In this study the effects of a pulsed excimer laser emitting at 308 nm (XeC1) on enamel susceptibility to artificial caries-like lesions were investigated. Additional effects of fluoride (F) application were also studied and SEM examinations performed. Sixty-four extracted human molar teeth were coated with acid resistant varnish leaving 4 windows, then sectioned, leaving one window on each tooth quarter. The windows were treated in one of the following ways: untreated (control), or lased, or exposed to 4 mm. APF(1.23% F) before lasing, or exposed to 4 mm. APF (1.23% F) after lasing. Laser parameters were: frequency: 1,25 Hz; pulse duration: 15 ns; fluence: 1, 5, 10, 30, 70, J/cm2; spot size: 5.0 mm2. After lasing, microhardness profiles were obtained and SEM was performed. Caries resistance was generally increased at moderate fluences. F application combined with lasing enhanced caries resistance at some parameters. SEM showed effects ranging from minimal to localized effects to extended glazing. Pulsed excimer laser irradiation, especially combined with topical F application can inhibit development of artificial caries-like lesions.