OBJECTIVE To determine the safety and efficacy of topical 0.03% tacrolimus ointment treatment for subepithelial corneal infiltrates (SEIs). METHODS This prospective non-controlled interventional case series included patients with SEIs who had been previously treated with topical corticosteroids with either no improvement or the medication being withdrawn due to associated intraocular pressure (IOP) elevation. The patients were treated with 0.03% tacrolimus ointment twice daily for 22 weeks (including a 1-month washout). The objective data were best-corrected Snellen visual acuity (BCVA), IOP, and full ocular examination results, including SEI severity and the Schirmer test. The subjective data were the patients' responses to a questionnaire at all follow-up visits. RESULTS The patients consisted of five males (45%) and six females (55%) (mean age 50 ± 11 years) who were followed up for an average of 22 weeks. The mean BCVA (logarithm of the minimum angle of resolution [logMAR]) before and after treatment was 0.34 ± 0.09 and 0.08 ± 0.04 respectively (p = 0.042). All the patients evidenced significant objective clinical improvement, and none had a severe degree of SEI at the end of the treatment. The patients reported considerable reduction in the severity of their symptoms (foreign body sensation, glare, etc.). Three patients were excluded due to side-effects (one had severe dizziness and discomfort), and their data were excluded from the study. CONCLUSIONS Topical tacrolimus 0.03% is a safe and effective alternative treatment in patients with SEIs who do not respond to other treatment modalities or have untoward side-effects from topical steroids.