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To assess the rejection episode rate after deep anterior lamellar keratoplasty (DALK) and to identify associated risk factors.This retrospective review of 251 primary DALK procedures performed by 14 surgeons at a single center between February 2008 and November 2015 evaluated the rejection episode rate and associated risk factors using Kaplan–Meier survival and proportional hazards analyses, which took the length of follow-up into consideration.Transplant indications were keratoconus or ectasia after laser refractive surgery (n = 170, 68%), corneal opacity (n = 72, 28%), and other anterior corneal disease (n = 9, 4%). The median recipient age was 46 years. The overall rejection episode rate was 14% with 18-month median follow-up and a 7-week median postoperative corticosteroid duration. In univariate analysis, increased risk of rejection episodes was associated with younger recipient age [relative risk (RR): 2.1, 95% confidence interval (CI): 1.4–5.2], African American race (RR: 2.1, 95% CI: 1.1–4.1), and use of manual trephination (compared with the femtosecond laser) for the side-cut incisions (RR: 2.7, 95% CI: 1.4–5.2). In multivariate analysis, the combined effect of patient age and race (P = 0.0012) and the side-cut method (P = 0.021) were each significant risk factors.This study demonstrates the substantial rate of rejection episodes that can be induced by corneal stroma in DALK and suggests that postoperative topical corticosteroids should be continued longer than the study's 7-week median and that young African Americans need higher-dose, longer-duration topical corticosteroids. The association between the side-cut method and rejection risk merits further investigation.