To describe regional variation in microbes causing infectious endogenous endophthalmitis (EE) in the United States.This is a retrospective, national database analysis utilizing the 2002-2014 National Inpatient Sample database.Using the International Classification of Disease 9 codes, we identified cases with EE. Cases were stratified regionally into Northeast, South, West, or Midwest.Unadjusted chi-square analysis followed by adjusted multivariate logistic regression was performed to evaluate variation in demographic factors, comorbidities using the Elixhauser Comorbidity Index (ECI), microbial variation, mortality, and use of vitrectomy or enucleation by region.Proportion of microbes, mortality, and vitrectomy by region in addition to factors with significant odds ratios for mortality and for in-hospital vitrectomy.A total of 10 912 patients with infectious EE were identified, with 2063 cases in the Northeast (18.9%), 2145 cases in the Midwest (19.7%), 4134 cases in the South (37.9%), and 2570 cases in the West (23.6%). Chi-square analysis indicated significant regional variation in patient demographics, microbes causing the infection, ECI, mortality, and surgical intervention. The 4 most common microbes for all regions were methicillin-sensitive Staphylococcus aureus (MSSA), Streptococcus, Candida, and methicillin-resistant Staphylococcus aureus. Methicillin-sensitive S. aureus was the most common cause of EE in all regions, although the proportion of MSSA infection did not significantly vary by region (P = 0.03). Further, there was significant regional variation in the proportion of other microbes causing the infection (P < 0.001). Higher rates of vitrectomies were seen in the South and Midwest regions than that in the Northeast and West (P = 0.04).Regional variation exists in the infectious microbes causing EE. Further studies are needed to elucidate the etiology of these variations.Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.