The aim of this study was to define risks for corneal transplantation associated with fibrous ingrowth among first-time transplant recipients. We performed a retrospective case-control study of patients with a histopathologic diagnosis of fibrous ingrowth between 2002 and 2019. Patients with fibrous ingrowth from a first corneal specimen were included. Those with incomplete records were excluded. A 1:2 case-control ratio was used. Controls were matched using surgical indication, surgery year, transplantation method, sex, and age. Seventy-eight eyes (76 patients) were included and matched with 160 control eyes. The incidence of fibrous ingrowth found on a first corneal transplant was 0.6% per year. The most common keratoplasty indications were pseudophakic corneal edema (n = 25, 32%) and aphakic corneal edema (n = 15, 19%). Cases were more likely to have a history of ocular trauma (odds ratio [OR], 2.94; 95% CI, 1.30-6.30; P = 0.007), uveitis (OR, 2.73; 95% CI, 1.12-6.63; P = 0.022), retinal detachment or previous retinal surgery (OR, 2.40; 95% CI, 1.34-4.30; P = 0.003), glaucoma tube-shunt surgery (OR, 2.70; 95% CI, 1.29-5.65; P = 0.007), aphakia (OR, 3.02; 95% CI, 1.61-5.67; P = 0.0004), or iris derangement (OR, 10.52; 95% CI, 5.45-20.30; P <0.0001). A multivariate logistic regression model using iris derangement, history of ocular trauma, history of uveitis, and history of cataract surgery demonstrated 81% sensitivity and 66% specificity in predicting presence of fibrous ingrowth. A history of ocular trauma, uveitis, retinal detachment or previous retinal surgery, glaucoma tube-shunt surgery, aphakia, and iris derangement are risks for detecting fibrous ingrowth among first-time keratoplasty recipients. Patients with these conditions should be monitored closely for corneal decompensation.