Purpose: To investigate whether any systemic medical conditions may be associated with a higher risk of developing postinjection endophthalmitis. Methods: This case-control study is a retrospective review within the Emory Eye Center between 2009 to 2019 and The Cleveland Clinic Foundation between 2012 to 2019. Each case was matched in a 1:4 case-to-control ratio. The associations between medical comorbidities and endophthalmitis were explored using multivariable logistic regression models on the combined sample. Results: Sixty-six individuals were diagnosed with injection-associated endophthalmitis. Systemic immunocompromised status was found to be a risk factor associated with developing endophthalmitis with an adjusted odds ratio (aOR) of 3.17 ( P = .009). Other conditions with increased risk approaching statistical significance included history of pulmonary disease (aOR, 1.74; P = .08) and a history of smoking (aOR, 1.72; P = .06). Conclusions: This is the first report to our knowledge demonstrating that immunocompromised status is associated with increased risk of developing postinjection endophthalmitis. While this study may be limited due to its retrospective nature, the result may nevertheless serve as a guidance for risk counseling. Future analysis using a large-scale database will be needed.