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PURPOSE To evaluate and compare the influence of the wound healing process at the graft edge on corneal biomechanics after primary penetrating keratoplasty (PK) and repeat PK. METHODS This retrospective comparative study included 95 eyes: 35 eyes of 35 patients had PK, 40 eyes of 40 patients underwent repeat PK, and 20 eyes of 20 normal subjects served as the control group. The ocular response analyzer was used to measure and compare corneal hysteresis and corneal resistance factor among the study groups at least 6 months after all sutures were removed. In vivo confocal microscopy was used to study the corneal wound healing process at the graft edge in PK and repeat PK groups and to correlate these findings with corneal biomechanics. RESULTS Corneal hysteresis and corneal resistance factor were significantly lower in the PK group (6.71 ± 1.3 and 5.99 ± 1.2 mm Hg, respectively) as compared with the repeat PK group (9.4 ± 1.03 and 8.77 ± 1.1 mm Hg, respectively) (P < 0.0001). The repeat PK group demonstrated biomechanical parameters comparable with normal subjects (9.88 ± 1.29 and 9.24 ± 1.13 mm Hg, respectively) (P = 0.12). Confocal microscopy revealed more reflective and activated keratocytes at the graft edge in the repeat PK group as compared with the primary PK group. CONCLUSIONS The healing process at the graft edge is the key to optimal corneal integrity after PK. Repeat PK stimulated more activated keratocytes than primary PK and hence a stronger healing response, providing superior corneal biomechanics comparable with normal subjects.