Genetic factors may interact with physical activity levels to modify obesity risk. Our aim was to explore the influence of rs1801260 single-nucleotide polymorphism (SNP) (3111T/C) of CLOCK gene on obesity risk, and to examine its potential interaction with lifestyle factors in an elderly population within the SUN ("Seguimiento Universidad de Navarra") Project. Subjects (n = 903, aged 69 ± 6 yrs) were recruited from the SUN Project. DNA was obtained from saliva, whereas lifestyle and dietary data were collected by validated self-report questionnaires. Genotype was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) plus allele discrimination. A significant interaction was observed between the 3111T/C SNP of CLOCK gene and sex for overweight/obesity risk (p for sex × CLOCK interaction <.001). Our results showed that women carrying the C allele of CLOCK gene had a marginally significant lower risk of overweight/obesity compared with noncarrier-TT-subjects (odds ratio [OR]: .61, 95% confidence interval [CI]: .36-1.04; p = .069). Moreover, this association of the C allele with a decreased overweight/obesity risk might be enhanced in those women with a high physical activity level. Women practicing more than 16.8 metabolic equivalent tasks (hours per week) had a significantly lower overweight/obesity risk (OR: .36, 95% CI: .17-.79; p = .011). Furthermore, a significant interaction between the 3111T/C gene variant and physical activity (PA) for overweight/obesity risk was observed but only in women (p for PA × CLOCK interaction <.050). In conclusion, it appears that physical activity levels may act by modifying the association of the 3111T/C SNP (rs1801260) of the CLOCK gene with overweight/obesity risk in elderly women in the SUN Project.