Purpose The corneal cap thickness is a vital parameter designed in small incision lenticule extraction (SMILE). The purpose was to investigate the changes in corneal subbasal nerve plexus (SNP) and stromal cells with different cap thicknesses and evaluate the optimized design for the surgery.Methods In this prospective, comparative, non-randomized study, a total of 108 eyes of 54 patients who underwent SMILE were allocated into three groups with different corneal cap thicknesses (110 mu m, 120 mu m or 130 mu m group). The SNP and stromal cell morphological changes obtained from in vivo corneal confocal microscopy (IVCCM) along with their refractive outcomes were collected at 1 week, 1 month, 3 months and 6 months postoperatively. One-way analysis of variance (ANOVA) was used to compare the parameters among the three groups.Results The SNPs in the three groups all decreased after surgery and revealed a gradual increasing trend during the 6-month follow-up. The values of the quantitative nerve metrics were significantly lower in the 110 mu m group than in the 120 mu m and 130 mu m groups, especially at 1 week postoperatively. No difference was detected between the 120 mu m and 130 mu m groups at any time point. Both Langerhans cells and keratocytes were activated after surgery, and the activation was alleviated during the follow-up.Conclusions The SMILE surgeries with 110 mu m, 120 mu m or 130 mu m cap thickness design achieved good efficacy, safety, accuracy and stability for moderate to high myopic correction while the thicker corneal cap was more beneficial for corneal nerve regeneration.