Forty-seven symptomatic inpatients and outpatients with major depression (13 nonendogenous, 23 endogenous, and 11 psychotic by Research Diagnostic Criteria) were compared with 138 normal control subjects. Absolute regional cerebral blood flow (rCBF, ml/minute/100 g) was measured with 133Xe single photon emission computed tomography. Flow ratios (region of interest/global flow) and residual scores (the difference between patient flow ratios and expected normal flow ratios, as derived from the control population) were also computed. Results revealed significant age x region x depression subtype interactions for absolute, ratio, and residual flow data. Consequently, a test of group means (or analysis of covariance) could not be used to examine between-group differences. Multiple regression analyses were employed to study the effects of age on rCBF. This analysis revealed that different, though sometimes overlapping, regions exhibited different age effects on rCBF in different depressive subtypes. Thus, diagnostic-subtype-dependent age effects on rCBF precluded comparisons of mean values within or across regions for subject groups, but distinguished between symptomatic depressed patients and control subjects and among patient groups. Possible causes of such effects include variations in duration of illness or medication history or sensitization phenomena.