Long-term treatment with lithium salts has been established as an effective prophylactic therapy in manic-depressive (bipolar) illness. Many patients, however, display a lack of (or partial) treatment response. We recently proposed that pharmacogenetic factors may influence and determine the therapeutic efficacy of lithium in bipolar disorder. The lithium-blockable enzyme inositol polyphosphate 1-phosphatase in the phospholipase C signaling pathway is a putative target for the mood-stabilizing effects of lithium. In the present study, we searched for DNA variations in the human INPP1 gene encoding the inositol polyphosphate 1-phosphatase enzyme. We report the existence of four common polymorphisms in the coding region of the gene. The DNA alterations were all single base substitutions, of which one (A682G) predicted an amino acid change (Thr228Ala), whereas the remaining three (G153T, G348A and C973A) were silent, In a Norwegian pilot sample the frequencies of the four single base substitutions were not significantly different between lithium-treated bipolar patients and healthy control individuals. When subdivided with respect to drug response, however, the C973A transversion was present in six out of nine lithium responders (67%) versus one out of nine non-responders (11%) In contrast, the C973A polymorphism was equally common among lithium responders and non-responders in an independent sample of bipolar patients from Israel. Future studies are therefore need to determine whether allelic variants of the INPP1 gene are associated with a favourable efficacy of lithium in manic-depressive illness.