© 2019 by the American Society of Nephrology. Background and objectives apo L1 (APOL1) nephropathy risk alleles are associated with CKD in blacks. Although APOL1 has innate immune functions, little is known about the association of APOL1 genotypes with risk of infectious outcomes, such as sepsis. The objective of this study was to examine the associations of APOL1 nephropathy risk alleles with risk of sepsis in black adults. Design, setting, participants, & measurements We assessed the association of APOL1 risk alleles with incident sepsis in 10,366 black participants of the Reasons for Geographic and Racial Differences in Stroke study enrolled between 2003 and 2007 with follow-up through December 31, 2012. In Cox models adjusted for demographics, comorbid conditions, and principal components ancestry, we examined the association of APOL1 risk alleles with incident sepsis using recessive (comparing zero or one versus two risk alleles), dominant (zero versus one or two risk alleles), and additive genetic models. We also examined models stratified by diabetes and CKD status. Results A total of 1320 (13%) participants had two APOL1 risk alleles, 4719 (46%) had one risk allele, and 4327 (42%) participants had zero risk alleles. A total of 306 sepsis events occurred over a median 6.5 years (interquartile range, 4.5–8.1). There were no statistically significant associations of APOL1 genotype with sepsis risk under recessive genetic models. APOL1 genotypes were associated with sepsis risk under dominant (hazard ratio, 1.55; 95% confidence interval, 1.13 to 2.11) and additive (hazard ratio per variant allele copy, 1.25; 95% confidence interval, 1.02 to 1.53) genetic models adjusted for covariates and ancestry. These associations did not vary by diabetes or CKD status (Pinteraction.0.10 for both). Conclusions In community-dwelling black adults, carriage of APOL1 nephropathy risk alleles are common and associated with higher risk of sepsis.