AbstractRecent studies showed that a polymorphism (T to C nucleotide substitution) in the 3′ flanking region of the human CLOCK gene is associated with diurnal preferences of human healthy subjects, with higher “eveningness” in subjects carrying at least one copy of the C allele. We investigated the possible role of CLOCK gene polymorphism in the regulation of diurnal mood fluctuations during a major depressive episode. Sample (n = 101) was collected, in the context of previously reported trials, among patients affected by bipolar disorder type I, depressive episode without psychotic features, free of psychotropic medications. Perceived mood levels were assessed three times a day with self‐administered visual analogue scales. Genotype groups showed no significant difference in diurnal mood fluctuations. When stratifying the sample by including only patients with an adequate period of observation (duration of illness higher than 5 years, n = 69), we post‐hoc observed a significantly higher recurrence rate in homozygotes for the C variant, which was almost double than that of the other genotype groups. This preliminary observation leads to hypothesize a role for the CLOCK gene polymorphism in the regulation of long‐term illness recurrence in bipolar disorder. Given the post‐hoc nature of the finding, replication in independent samples is necessary to confirm it. © 2003 Wiley‐Liss, Inc.