We have examined red blood cell (RBC) thiopurine methyltransferase (TPMT) activity in a healthy population sample of Norwegian children, age 1-10 years. Boys had mean RBC TPMT activity of 11.1 +/- 2.0 U (n = 87) vs. 10.6 +/- 2.2 U (n = 71) in girls, the difference was not significant (P = 0.3). Age was negatively correlated to RBC TPMT activity (rs = -0.2, P = 0.01). As boys with acute lymphoblastic leukemia (ALL) tolerate more 6-mercaptopurine (6-MP) than girls and have a higher risk of relapse, we have searched for pharmacokinetic causes of these gender differences. The gender difference in 6-MP tolerance and clinical outcome in children with ALL cannot be explained by the minor and nonsignificant higher RBC TPMT activity in boys compared to girls.