Rasburicase-induced methemoglobinemia is a known adverse effect of patients administered rasburicase for tumor lysis syndrome who have concomitant glucose-6-phosphate dehydrogenase deficiency. This phenomenon has been described in multiple case reports but has been limited to male patients. We present the first case series illustrating this adverse effect in two female patients where morbidity and mortality associated with rasburicase-induced methemoglobinemia were evident. Screening protocols at the reporting institutions were lacking. The prevalence of G6PD may be underestimated based on the epidemiology of sample subjects in previous studies of rasburicase. We argue that both male and female patients should be suspected of G6PD in this setting; however, more data on prevalence and cost-effectiveness are needed on screening protocols for G6PD.