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Background: Sulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However there exists significant variability in glycaemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA1c reduction. Methods: As an initiative of the Metformin Genetics Plus (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortia, 5,485 white European adults with type 2 diabetes treated with sulfonylurea were recruited from 6 referral centres in Europe and North America. We first estimated heritability using generalized restricted maximum likelihood (REML) and then undertook GWAS of glycemic response to sulfonylureas measured as HbA1c reduction after 12 months of therapy in each cohort using linear regression followed by meta-analysis. These results were supported by cis-eQTLs and functional validation in cellular models. Findings: After establishing that sulfonylurea response is heritable (37±11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA1c reduction. The C-allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), p=2.4×10−8) lower HbA1c reduction. Similarly, the C-allele was associated with higher glucose trough levels (β=1.61, p=0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). The C-allele of rs10770791, near SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater HbA1c reduction (p=4.8×10 −8 ). In 1,183 human liver samples, the C-allele at rs10770791 is a cis-eQTL for reduced SLCO1B1 expression (p=1.61×10−7) which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use, sulfonylurea response and SCLO1B1 genotype was observed (p=0.001). In statin non-users (but not users), C-allele homozygotes at rs10770791 had a large absolute reduction in HbA1c (0.48±0.12% (5.2±1.26 mmol/mol)), equivalent to initiating a DPP4 inhibitor. Interpretation: We have identified clinically important genetic effects at genomewide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important when prescribing glucose-lowering drugs. Funding Statement: Innovative Medicines Initiative, the National Institutes of Health, the Geisinger Health Plan Quality Pilot Fund. Declaration of Interests: ERP has received honoraria for speaking from Lilly and Sanofi. JCF has received honoraria for speaking at scientific conferences from Novo, and for consulting from Goldfinch Bio. All other authors declare no competing interest. Ethics Approval Statement: This study was approved by respective research ethics review boards and participants provided written informed consent.