Non-Hodgkin's lymphomas (NHL) are usually sensitive to chemotherapy. A certain percentage of patients are primarily or subsequently resistant to chemotherapeutic agents. Several biological mechanisms are implicated in this phenomenon, including multidrug resistance (mdr1) and glutathione S-transferase (GST pi). We investigated these two systems, using dot blot analysis, in 41 patients who presented NHL with advanced disease. There were 15 patients with low grade, 22 with intermediate grade, and 4 patients with high grade using the Working Formulation for Clinical Usage. Twenty-five patients had not been previously treated and 16 had been treated, including 13 with refractory disease. Eleven out of 25 (44%) patients overexpressed mdr1 mRNA at diagnosis as compared to 6/16 (38%) in relapse, corresponding to 6/13 (46%) refractory patients. Nine out of 25 (36%) patients overexpressed GST pi mRNA at the time of diagnosis, and 6/16 (50%) in relapse. These data indicate that overexpression of these two messengers is not acquired after treatment in NHL. Furthermore, there is no relationship between the stage or histological grade and the overexpression of these two markers. This study shows that mdr1 and GST pi gene expressions are independent of one another. With regard to the clinical response, our results also demonstrated a higher level of treatment failure in the group co-expressing the two transcripts, 6/8 (75%) patients died in progressive disease as compared to 9/15 (60%) patients without overexpression, and 2/8 (25%) vs 6/15 (40%) responded to treatment. On the other hand, overexpression of only one of the two mRNAs did not allow us to observe a difference in the clinical response. Since it seems that coexpression of the mechanisms of resistance present a better clinical impact, it would be of interest to analyse simultaneously different mechanisms involved in the resistance phenomenon in NHL.