Impairment of cognition is common in depression, and many tasks on which depressed patients are impaired are sensitive to frontal lobe dysfunction. Performance on the Tower of London (TOL) task, which includes setting up and maintaining multiple subgoals at the same time, has been shown to depend on intact prefrontal cortices. Single photon emission computed tomography (SPECT) with 99mTc-ethyl cysteinate dimer was used to compare cognitive activation in nine depressed patients and nine normal controls during performance of the TOL task. Planning times and accuracy were measured as performance parameters, and functional imaging data were analysed with statistical parametric mapping (SPM99) to determine significant voxel-wise differences in activation between the two groups. During activation, depressed patients were as accurate as controls but differed in that they spent more thinking time. These findings agree with the results of neuropsychological studies. Compared with the normal controls, depressed patients were characterized by a blunted perfusion response in the right middle frontal cortex [Brodmann area (BA) 6] and the left superior frontal gyrus (BA 9), and by increased perfusion in the right superior temporal gyrus (BA 21) and the insular cortex (BA 13). This study shows that a SPECT activation procedure using the TOL task under classical test conditions is feasible in depressed patients.