Abstract. Chronic manganese (Mn) exposure causes a variety of psychiatric and motor disturbances, termed manganism. Here, we provide an evidence to support the involvement of the calcium-dependent proteases, calpains, in the pathogenesis of manganism in a rat model. 20 male rats were divided randomly into two groups: the control group and the Mn exposure group. The rats in the Mn exposure group received intranasal injection of 1 mg/rat MnCl 2 ×4H 2 O once a day for 90 days. The control group rats received intranasal injection of physiological saline the same way. The levels of Mn in the striatum (Str) were assessed using atomic absorption spectroscopy. Mn levels were found to be significantly higher in the experimental group of rats than in the control group. Further, the involvement of calpain-1 and calpain-2 was monitored in the Str. The activity of calpain-1/2 was determined by casein zymography. It was revealed, that Mn induced an increase of the activity of calpain-2 in the Str, where the activity of calpain-1 was also increased. We have also shown that Mn directly activates calpain-1 like calcium but not calpain-2. We propose that calpains can be potential therapeutic targets for manganism.