BACKGROUND: Thiopurines are an important class of immunosuppressants despite their risk for hematopoietic toxicity and narrow therapeutic indices. Benign neutropenia related to an ACKR1 variant (rs2814778-CC) is common among individuals of African ancestries. OBJECTIVE: We tested whether rs2814778-CC was associated with azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine dosing. DESIGN: Retrospective cohort study. SETTING: Two tertiary care centers. PATIENTS: Thiopurines users with White or Black race. MEASUREMENTS: Azathioprine discontinuation attributed to hematopoietic toxicity. Secondary outcomes included weight-adjusted last dose, white blood cell (WBC) and delta WBC counts. RESULTS: The discontinuation rate of azathioprine attributed to hematopoietic toxicity was 3.92/100 person-years among patients with the CC genotype (n=101) and 1.34/100 person-years among patients without the CC genotype (n=1,365) [hazard ratio (HR)=2.92, 95%CI: 1.57–5.41, competing hazards model]. The risk remained significant when adjusted by race (HR=2.61, 1.01–6.71). The risk associated with race alone (HR=2.13, 1.21–3.75) was abrogated by adjustment for genotype (HR=1.13, 0.48–2.69). Lower dosing and other secondary outcomes, except delta WBC count, were significant among patients who did not discontinue for hematopoietic toxicity. Lower dosing was validated in an external cohort of 94 children of African ancestries prescribed the thiopurine 6-mercaptopurine (6-MP) for acute lymphoblastic leukemia (ALL). The CC genotype was independently associated with lower 6-MP intensity dosages relative to the target daily dose—75 mg/m(2) (CC: median 0.83 interquartile range [0.70–0.94] vs TT or TC: 0.94 [0.73–1.13], P=0.013). LIMITATIONS: Unmeasured confounding. Data limited to tertiary centers. CONCLUSION: Patients with the CC genotype faced higher risk for discontinuation for attributed hematopoietic toxicity and lower doses. Genotype, even adjusted for race, is associated with those risks. PRIMARY FUNDING SOURCE: National Institutes of Health