Cathepsins are lysosomal enzymes that are used as sensitive markers in various toxicological investigations. The purpose of this study was to evaluate and compare the influence of cimetidine and famotidine on the cerebral cortex, particularly on the activity of cortical cathepsin B, D and L in the frontal lobe of rat brain. The drugs were administered intraperitoneally, twice a day, for six weeks to male Wistar rats in two doses. The initial dose was 2.85 mg/kg for cimetidine and 0.285 mg/kg for famotidine. The second dose was 10 times higher. Control animals were injected with 0.9% NaCl. Half of the animals from each of the drug-treated and control groups were sacrificed on the 42nd day of the experiment. The remaining animals were raised for another 6 weeks without any xenobiotics, and sacrificed on the 84th day. The frontal lobe of the right cerebral hemisphere was taken for biochemical investigation. The activities of free and bound fractions of cathepsin B, D and L were evaluated spectrophotometrically in cortical homogenates. The activity of bound fraction of cathepsin D and L decreased significantly in animals exposed to the higher dose of cimetidine and sacrificed on the 42nd day. Also significant elevation of the free fraction of cathepsin L was noted in the same group of rats. Cathepsin activities were normalized during the next six weeks. No behavioural changes were noted among the observed animals. Unlike cimetidine, famotidine did not change profiles of the cerebral cathepsins.