The aim of the study was to evaluate and compare the surface microhardness and surface morphology of permanent tooth enamel after Er,Cr:YSGG laser irradiation and Fluoride application. One hundred and twenty premolars extracted for orthodontic purpose were used in the study and randomly divided into 6 groups. Group A was not subjected to any treatment. Group B was subjected to Er,Cr:YSGG laser irradiation. Group C was subjected to Er,Cr:YSGG laser irradiation followed by application of 2% NaF gel for 4 minutes. Group D was subjected to laser irradiation and 1.23% APF gel for 4 minutes. Group E was subjected to 2% NaF gel pretreatment technique followed by laser irradiation. Group F was subjected to 1.23% APF gel pretreatment technique followed by laser irradiation. All the test groups were subjected to microhardness testing and scanning electron microscope evaluation at 500 X and 1500 X. All the treated groups showed an increase in microhardness value in comparison to the control group. The highest increase in microhardness was seen in Group F. Increase in microhardness values of Group B and Group D was not statistically significant as compared to Group A. Scanning Electron Micrographs showed few craters and fine porosities for Group A. These craters and porosities increased in size and often showed glass like appearance after laser irradiation. It can be suggested by means of present study that Er,Cr:YSGG laser irradiation alone or in combination with fluoride gel is an effective tool to provide resistance against the caries. Significantly higher resistance (p< 0.05) was seen when APF gel was used prior to Er,Cr:YSGG laser irradiation and this combination can act as an efficient tool for prevention against dental caries.