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OBJECTIVE: Metformin is the most common treatment for type 2 diabetes (T2D). However, there have been no pharmacogenomic studies for T2D in which a population of color was used in the discovery analysis. This study sought to identify genomic variants associated with metformin response in African American patients with diabetes. RESEARCH DESIGN AND METHODS: Patients in the discovery set were adult, African American participants from the Diabetes Multi-omic Investigation of Drug Response (DIAMOND), a cohort study of patients with T2D from a health system serving southeast Michigan. DIAMOND participants had genome-wide genotype data and longitudinal electronic records of laboratory results and medication fills. The genome-wide discovery analysis identified polymorphisms correlated to changes in glycated hemoglobin (HbA1c) levels among individuals on metformin monotherapy. Lead associations were assessed for replication in an independent cohort of African American participants from Kaiser Permanente Northern California (KPNC) and in European American participants from DIAMOND. RESULTS: The discovery set consisted of 447 African American participants, whereas the replication sets included 353 African American KPNC participants and 466 European American DIAMOND participants. The primary analysis identified a variant, rs143276236, in the gene ARFGEF3, which met the threshold for genome-wide significance, replicated in KPNC African Americans, and was still significant in the meta-analysis (P = 1.17 × 10−9). None of the significant discovery variants replicated in European Americans DIAMOND participants. CONCLUSIONS: We identified a novel and biologically plausible genetic variant associated with a change in HbA1c levels among African American patients on metformin monotherapy. These results highlight the importance of diversity in pharmacogenomic studies. [ABSTRACT FROM AUTHOR]