Lithium has established itself as an effective prophylactic agent in mood disorders, but not all patients respond to lithium therapy. It is probable that genetic factors play a substantial role in determining the differences in response to lithium. The aim of this study was to investigate the association between the dopamine receptor D3 (DRD3) gene and prophylactic efficacy of lithium in mood disorders. Fifty-five subjects affected by bipolar (n = 43) and major depressive (n = 12) disorder were followed prospectively for an average of 49 months and were also typed for their DRD3 variant, using polymerase chain reaction techniques. DRD3 variants were not associated with lithium outcome. Consideration of possible stratification effects, such as gender, polarity, family history, age at onset or duration of lithium treatment, also did not reveal any associations. DRD3 variants are not, therefore, a major factor influencing the prophylactic efficacy of lithium in mood disorders.