Abstract The aim of our study was to investigate gene variants in the long-term outcome of mood disorders. We retrospectively studied a sample of inpatients affected by recurrent and rapid cycling mood disorders. The serotonin transporter gene-linked functional polymorphic region (5-HTTLPR) and the A218C tryptophan hydroxylase (TPH) gene variant were determined using a PCR-based technique. For 5-HTTLPR polymorphism we genotyped 435 inpatients affected by major depressive ( n=153), bipolar ( n=213) and rapid cycling ( n=69) mood disorders and 456 controls; for TPH we genotyped 399 inpatients (MD, n=132; BP, n=203; rapid cycling n=64) and 259 controls. Random Regression Model analysis was used to investigate the longitudinal time course of the illness. 5-HTTLPR and TPH polymorphisms were not associated with mood disorders time course. However we observed an excess of 5-HTTLPR*long alleles among rapid cycling subjects compared to both controls ( P=0.018) and remitting mood disorders ( P=0.006). TPH frequencies did not differ between mood disorders subtypes. Our results suggest that 5-HTTLPR variants may confer a susceptibility toward rapid cycling mood disorders.