Background Increasing the resistance of enamel to acids may prevent dental erosion and diminish microhardness alterations in the enamel. This study aimed to evaluate the preventive effect of erbium, chromium: yttrium, scandium, gallium, and garnet laser combined with 1.23% acidulated phosphate fluoride gel on enamel resistance to demineralization. Material and Methods Thirty-four human maxillary first premolars were randomly assigned to three groups. Group I (control group), group II were treated with fluoride gel for 4-minutes and group III received ten seconds of laser treatment; then fluoride has applied. Each sample was immersed in a soft drink for 2 minutes, then washed and kept in deionized water. Four consecutive cycles were carried out at 6 hours intervals. The effects were studied utilizing the Vickers microhardness test and scanning electron microscopy. Data analyses were performed by Levene test and General Linear Model Repeated Measure Factorial ANOVA with Bonferonni post hoc test, the accepted level of significance was 0.05. Results Microhardness was increased statistically in groups II and III after treatment, with the highest value for group III. After demineralization, the control group had the lowest microhardness score, followed by group II and group III, which showed the least reduction in microhardness with a statistical significance ( p <0.05). There was a correlation between the morphological alterations in enamel surfaces and the increased enamel resistance. Conclusions Both fluoride and the combined laser fluoride treatment had an advantage in protecting the enamel and increasing enamel resistance to acids, with a more significant benefit for the combined laser fluoride group. Key words: Prevention, Er, Cr: YSGG, enamel demineralization, fluoride, microhardness.