• Adherence rates were significantly lower in African Americans (87%) and Asian Americans (90%), as compared with non-Hispanic whites (95%).• Adherence to 6MP at ,90%was associated with a 3.9-fold increased risk of relapse in a multiracial cohort of children with ALL.Durable remissions in children with acute lymphoblastic leukemia (ALL) require a 2-year maintenance phase that includes daily oral 6-mercaptopurine (6MP . Adherence rate below 90% was associated with increased relapse risk (hazard ratio, 3.9; P 5 .01). Using an adherence rate <90% to define nonadherence, 20.5% of the participants were nonadherers. We identify race-specific determinants of adherence, and define a clinically relevant level of adherence needed to minimize relapse risk in a multiracial cohort of children with ALL. This trial was registered at www.clinicaltrials. gov as #NCT00268528. (Blood. 2014;124(15):2345-2353