This study investigated the combined effect of fractional CO(2) laser irradiation and fluoride on treatment of enamel caries. Sixty intact premolars were randomly assigned into four groups and then stored in a demineralizing solution to induce white spot lesions. Tooth color was determined at baseline (T1) and after demineralization (T2). Afterwards, the teeth in group 1 remained untreated (control), while group 2 was exposed to an acidulated phosphate fluoride (APF) gel for 4 min. In groups 3 and 4, a fractional CO(2) laser was applied (10 mJ, 200 Hz, 10 s) either before (group 3) or through (group 4) the APF gel. The teeth were then immersed in artificial saliva for 90 days while subjected to daily fluoride mouthrinse and weekly brushing. Color examinations were repeated after topical fluoride application (T3) and 90 days later (T4). Finally, the teeth were sectioned, and microhardness was measured at the enamel surface and at 30 and 60 μ from the surface. In both lased groups, the color change between T1 and T4 stages (∆E(T1-T4)) was significantly lower than those of the other groups (p < 0.05). Laser irradiation followed by fluoride application (group 3) caused a significant increase in surface microhardness compared to APF alone and control groups (p < 0.05). Microhardness at depths of 30 and 60 μ was also significantly greater in group 3 compared to those of all other groups (p < 0.05). Application of a fractional CO(2) laser before fluoride therapy is suggested for recovering the color and rehardening of demineralized enamel.