Background: Voltage-gated Na + channels (VGSCs) are involved in cells signalling and strongly contribute in the process of tumour progression. Two single nucleotide polymorphisms (SNPs) in the SCN1A gene encoding the α-subunit of VGSC recently showed an interesting gender-related association with survival in patients with metastatic colorectal cancer (CRC). The current study was designed to confirm the association between SCN1A and time to recurrence (TTR) in patients with stage II and III CRC and determine the influence of the gender on this association. Methods: The study enrolled patients with histologically confirmed CRC high risk stage II and stage III treated from 1987 to 2007 with adjuvant 5-FU-based chemotherapy at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC) or in the Los Angeles County/USC Medical Center (LAC/USCMC). Peripheral blood samples were collected for each patient at the date of diagnosis. Genotypes were determined after DNA extraction and PCR amplification by direct sequencing. Results: A total of 127 males and 107 females were enrolled in this study. Baseline demographic and clinical characteristics according to the gender were similar. In univariate analysis female patients carrying the SCN1A rs3812718 TT genotype showed a significant shortened time to recurrence rate when compared to females with the alternate CT or CC genotype (HR: 2.26 [95%CI: 0.89, 5.70], p=0.039). This association remained significant in multivariate analysis. By contrast, in the male population, the shortened time to recurrence rate was oppositely associated with the CC genotype (HR: 0.49 [95%CI: 0.18, 1.38], p=0.048). For the SCN1A rs229877, in both female and male populations the CT genotype was associated with a trend for a shorter TTR. Conclusions: Our findings confirm that genomic SCN1A rs3812718 polymorphism is associated with TTR in patients with stage II and III CRC, supporting the hypothesis that this association is gender dependent. We furthermore verified the trend of a shorter recurrence rate for patients harboring the CT genotype in SCN1A rs229877 regardless of their gender.