The exact role of the enzyme glycogen synthase kinase 3beta (GSK-3beta) in mood disorders is still unknown. GSK-3beta has been mapped to chromosome 3q13.3, a potential susceptibility locus for bipolar disorder. The -50T/C polymorphism, falling within the promoter region of the gene coding for GSK-3beta, was previously reported to be associated with age at onset, therapeutic response to lithium salts and total sleep deprivation in bipolar patients. In the present study we investigated the association between the -50T/C polymorphism and both symptomatic and personality features in mood disorders. The sample comprised 365 inpatients affected by major depressive disorder and bipolar disorder, genotyped for the GSK-3beta-50 polymorphism and assessed with the Operational Criteria Checklist for Psychotic Illness (OPCRIT). Ninety-five subjects were also evaluated with the Temperament and Character Inventory (TCI). The GSK-3beta-50 polymorphism showed a positive association with delusional symptomatology and with the personality features linked to Self-Transcendence. Finally, GSK-3beta-50 and personality showed an interactive effect on delusional scores. In conclusion, our findings support the role of GSK-3beta-50 in both normal and psychopathological aspects of human cognition and further suggest a possible interaction between genes and personality in the liability to psychotic disorders.