We have previously reported that children with B-precursor acute lymphoblastic leukemia (ALL) who remained in remission after successfully completing therapy had leukemia cells detectable by polymerase chain reaction (PCR) (N Engl J Med 1997;336(5):317-23). These patients were treated by an institutional protocol (P89-04) that lacked the post-remission intensification features of the contemporary Berlin-Frankfurt-Münster (BFM) based ALL protocols. In this report, we compared residual leukemia levels for patients on the P89-04 (n=15) and BFM-based Children's Cancer Group (CCG) studies (n=23) and for patients stratified according to risk group. Our goal was to establish which risk factors correlated with level of residual disease. Patients enrolled on the CCG protocols had lower levels of residual disease after completion of therapy than the P89-04 patients (P<0.019). Patients with high-risk disease also had lower levels of residual disease than patients with low risk disease (P<0.0001). Three-way analysis including time off treatment, risk group determined by features at presentation, and treatment protocol showed that risk group was the only significant independent variable (P<0.001).