Plasma levels of maprotiline, zimelidine, and their respective demethylated metabolites were analyzed, and their relationship to the clinical response was examined, in 60 depressed patients given the drug treatment for 4 weeks. Significant correlation was found between zimelidine and norzimelidine levels (r = 0.531; p less than 0.05) as well as between the steady-state levels of total zimelidine and concentration of the drug 12 h after a single dose (r = 0.753; p less than 0.001). The ratios of drugs and their metabolites in individual patients remained remarkably constant throughout the study. Significant correlations between Hamilton Depression Rating Scale (HAMD) scores and plasma levels of total maprotiline (r = 0.613; p less than 0.05) or norzimelidine (r = -0.552; p less than 0.05) were observed in subgroups of retarded depressives on day 14, and between HAMD scores and norzimelidine levels in retarded depressives (r = 0.703; p less than 0.02) and all patients (r = 0.436; p less than 0.02) on day 28. Both maprotiline and zimelidine produced marked decreases in mean HAMD scores by the end of treatment, but the overall clinical response between the various subgroups was not significantly different (x2 = 3.15; df = 3). Responders and nonresponders to treatment could not be distinguished by mean plasma levels of drugs or their metabolites when all patients were considered. However, a significant difference was found in maprotiline levels between responders and nonresponders within a subgroup of retarded depressives.