BACKGROUND: The Duffy glycoprotein (Fy) on red blood cells (RBCs) has been hypothesized to promote clearance of inflammatory cytokines, which may play a role in the pathogenesis of vasoocclusion in sickle cell disease (SCD). Persons with the African‐type Fy(a–b–) phenotype—whose RBCs lack expression of Duffy—may less efficiently clear inflammatory cytokines. Therefore, the Duffy‐negative genotype may be associated with more severe disease among patients with SCD.STUDY DESIGN AND METHODS: Genotyping was performed on blood samples from 249 adult patients with HbSS at the Duffy gene (FY) locus GATA site (rs2814778) that determines RBC expression of Duffy antigens. Patients with discordant genotype and phenotype data were excluded (n = 12). Differences in demographic, clinical and laboratory findings, end‐organ damage, and overall disease severity were compared between FY+ and FY– patients.RESULTS: Of the 237 patients studied, 174 (73%) were FY–. FY+ patients had a higher mean white blood cell (WBC) count (13.2 × 109 ± 4.1 × 109/L vs. 11.8 × 109 ± 3.3 × 109/L; p = 0.03) and higher rates of treatment with hydroxyurea (72% vs. 49%; p = 0.002). In contrast, FY– status was strongly associated with chronic organ damage (85% of FY– patients vs. 65% of FY+ patients; p = 0.018) and proteinuria (32% vs. 12%; p = 0.02). These associations remained, even after controlling for the effects of age and sex.CONCLUSIONS: Duffy genotype may be a potential biomarker for the development of end‐organ damage in SCD, particularly kidney dysfunction. The association of both WBC counts and hydroxyurea use with Duffy expression provides another avenue for investigation of the biologic role of this protein.