Inhibition of inositol monophosphatase (IMPase) enzyme is the target mechanism of action of lithium. However, increased activity of mRNA levels by lithium has been reported. These two diverse effects were shown after relatively short periods of lithium administration. The aim of this study was to observe the effect of prolonged use of lithium on IMPase activity. The authors investigated IMPase activities in fresh erythrocytes and leukocytes in 63 bipolar patients (42 euthymic, 8 depressive, 13 manic episodes) and 16 control subjects. We found that erythrocyte IMPase activity was higher in lithium treated euthymic patients than non-lithium treated patients. The duration of lithium use was positively correlated with leukocyte IMPase activity. Increased IMPase activity by chronic lithium use suggests an up-regulation of the enzyme activity.