Objective: In order to preserve the maximum amount of healthy enamel and increase the acid resistance of decalcified enamel, a CO2 laser, an Nd:YAG laser, and acidulated phosphate fluoride (APF) were used to treat incipient carious lesions, then their effects were compared. Materials and Methods: One hundred and sixty samples of human caries-free premolars were immersed in pH-cycling solution (pH = 5) for 2 d for decalcified lesion formation. Then the tooth samples were randomly divided into eight groups and the lesions were treated using the different modalities: a control group, an APF only group, an APF + Nd: YAG laser group, and APF + CO2 laser group, an Nd: YAG laser + APF group, a CO2 laser + APF group, a CO2 laser only group, and an Nd: YAG laser only group. The energy density setting for the two types of lasers was 83.33 J/cm(2). After treatment the tooth samples were immersed in pH-cycling solution again for 2 d for acid challenge. As for the acid-resistance evaluation, the calcium concentration dissolved from the enamel surface was analyzed by an electrolyte analyzer. Scanning electron microscopy (SEM) was used to assess morphologic changes and polarized light microscopy (PLM) was used to evaluate optical changes in the lesions. Results: The control group showed a statistically significantly (p < 0.05) higher calcium concentration compared with all the other groups. The APF group also had a statistically significantly higher calcium concentration (p > 0.05) than did the laser groups. However, there was no statistically significant difference in any of the laser groups whether combined with fluoride or not (p < 0.05). Upon SEM analysis, melted surfaces and crater-like holes 1-20 mu m in diameter were found in the CO2 laser and Nd: YAG laser groups. On PLM, positive birefringence and reversal of birefringence after acid challenge of the lased enamel were seen. Conclusions: Using lasers and fluoride on decalcified enamel appears to increase the enamel's acid resistance, and the effects of the lasers were better than those of fluoride treatment.