AbstractCircadian disruption is theorized to cause immune dysregulation, which is the only established risk factor for non‐Hodgkin's lymphoma (NHL). Genes responsible for circadian rhythm are also involved in cancer‐related biological pathways as potential tumor suppressors. However, no previous studies have examined associations between circadian genes and NHL risk. In this population‐based case control study (n = 455 cases; 527 controls), we examined the only identified nonsynonymous polymorphism (Ala394Thr; rs2305160) in the largest circadian gene, neuronal PAS domain protein 2 (NPAS2), in order to examine its impact on NHL risk. Our results demonstrate a robust association of the variant Thr genotypes (Ala/Thr and Thr/Thr) with reduced risk of NHL (OR = 0.66, 95% CI: 0.51–0.85, p = 0.001), especially B‐cell lymphoma (OR = 0.61, 95% CI: 0.47–0.80, p ≤≤ 0.0001). These findings provide the first molecular epidemiologic evidence supporting a role of circadian genes in lymphomagenesis, which suggests that genetic variations in circadian genes might be a novel panel of promising biomarkers for NHL and warrants further investigation. © 2006 Wiley‐Liss, Inc.