Lithium is an effective prophylactic agent in mood disorders but not all patients with mood disorders respond to lithium therapy; it is therefore necessary to identify responders prior to treatment. Clinical predictors account for about half of the variance and it is probable that genetic factors play a substantial role. The aim of this study was to investigate the possible association between the tryptophan hydroxylase (TPH) gene and prophylactic efficacy of lithium in mood disorders. One hundred and eight subjects affected by bipolar (n = 90) and major depressive (n = 18) disorder were followed prospectively for an average of 50.4 months and were typed for their TPH variant using polymerase chain reaction techniques. TPH variants were marginally associated with lithium outcome (F = 3.16; d.f.=2,105; P = 0.046). Subjects with the TPH*A/A variant showed a trend toward a worse response compared to both TPH*A/C and TPH*C/C variants. Consideration of possible stratification effects such as gender, polarity or age at onset did not influence the observed association. TPH variants may be a possible factor influencing the prophylactic efficacy of lithium in mood disorders.