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Sequential therapeutic penetrating keratoplasty (TPK) using a cryopreserved cornea followed soon after by a fresh optical grade cornea for severe infectious keratitis may improve the survival of the optical graft. The aim of this study was to compare the therapeutic efficacy, visual outcomes, and graft survival for sequential TPK against TPK using a fresh optical grade cornea alone.This was a retrospective case-control study. Case records were reviewed for clinical and surgical outcomes.Thirty-two eyes of 32 patients were included. Ten eyes underwent sequential TPK (TPK cases), and there were 22 age- and sex-matched controls, which underwent TPK with optical grade tissue alone. The mean interval between the TPK with the frozen cornea and the subsequent optical keratoplasty in the TPK cases was 16.8 ± 12.9 days. Therapeutic success, defined as the eradication of the primary infection, was achieved in all the TPK cases but only in 13 controls (59.1%) (P = 0.06). Graft survival at 1 year was better in the TPK cases than the controls (72.9% vs 53.8%). An improvement in Snellen acuity by at least 2 lines was more likely in the TPK cases than the controls (80% vs 14%; P = 0.001).Sequential TPK is an effective surgical therapy for active severe infectious keratitis and also helps to conserve valuable optical grade corneal tissue.