The current study investigated the anti-inflammatory effect of 0.1% tacrolimus eye drops for the treatment of therapeutic penetrating keratoplasty (TPK) for severe infectious keratitis during early disease stages and reported the long-term clinical outcomes. The present retrospective study included 20 eyes from patients diagnosed with severe keratitis who underwent TPK surgery. Patients were followed-up for up to 12-18 months. Tacrolimus eye drops were administered 4 times/day starting on the first day post-surgery. Glucocorticoid eye drops were subsequently added to treatment plans one-month post-surgery. All patients were followed-up for the first 3 post-operative days, then examined once a week thereafter for the first month. In early post-operative stages, the states of the grafts (Delta S) and the absorption of intraocular inflammation (S) were observed. Delta S was defined as the difference between the states of the grafts on the first post-operative day (SS1d) and those at one month post-surgery (SS1m). S was calculated as the difference between the inflammation score mean one day post-surgery (T1d) and the mean one-month post-surgery (T1m). For long term clinical outcomes, graft failure rates and complications were recorded. Among the 20 eyes analyzed, the mean T1d, T1m and S were 7.4 +/- 2.06, 2.0 +/- 2.47 and 5.4 +/- 2.13 (P<0.01), respectively. The mean SS1d, SS1m and <Delta>S were 5.3 +/- 1.56, 3.8 +/- 1.24 and 1.5 +/- 1.5 (P<0.01), respectively. During follow-up, there were 6 cases of corneal graft failure, 4 of which were due to immune rejection and 2 of which were due to complications. The current study concluded that tacrolimus eye drops facilitated the absorption of intraocular inflammation in the early post-operative period of TPK and may extend long term survival of grafts in cases of severe infectious keratitis.