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Rationale & Objective: Apolipoprotein L1 (APOL1) high-risk variants are associated with an increased risk for chronic kidney disease (CKD) among African Americans. Less is known regarding the risk for the development of CKD and kidney failure (end-stage kidney disease [ESKD]) among African Americans with only 1 APOL1 risk variant or whether the risk is modified by sickle cell trait. Study Design: The Jackson Heart Study is a community-based longitudinal cohort study. Setting & Participants: Self-reported African Americans in the Jackson Heart Study (n = 5,306). Exposures: APOL1 G1 and G2 genotypes and sickle cell trait. Outcomes: Incident CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m2), albuminuria (urinary albumin-creatinine ratio ≥ 30 mg/g), continuous and rapid kidney function decline (≥30% decline), and incident ESKD. Analytical Approach: Multivariable linear and logistic regression, and Cox proportional hazards models adjusted for age, sex, hypertension, diabetes, ancestry informative markers, and sickle cell trait. Results: Of 2,300 participants, 41.3% had zero, 45.1% had 1, and 13.6% had 2 APOL1 risk variants. Sickle cell trait was present in 8.5%. Compared with participants with zero APOL1 risk variants, those with 2 alleles had an increased risk for incident albuminuria (adjusted HR [aHR], 1.88; 95% CI, 1.04 to 3.40), ESKD (aHR, 9.05; 95% CI, 1.79 to 45.85), incident CKD (aHR, 1.65; 95% CI, 1.06 to 2.57), continuous decline (β = −1.90; 95% CI, −3.35 to −0.45), and rapid kidney function decline (OR, 2.21; 95% CI, 1.22 to 4.00) after adjustment for sickle cell trait, with similar results after adjustment for ancestry informative markers. Having 1 APOL1 risk variant was not associated with CKD outcomes and there was no interaction of APOL1 with sickle cell trait. Limitations: Single-site recruitment of African American individuals with APOL1 and sickle cell trait. Conclusions: The presence of 1 APOL1 risk allele was not associated with increased risk for CKD outcomes, whereas 2 risk alleles were associated with incident albuminuria, CKD, ESKD, and rapid and continuous kidney function decline. Additional studies are needed to determine factors that might alter the risk for adverse kidney outcomes among individuals with high-risk APOL1 genotypes.