In this nested case-control study, we demonstrated prospective associations of hypomethylation at AHRR, 6p21.33, and F2RL3 with LC incidence, which persisted after controlling for lifetime cumulative smoking exposure and various other potential confounders, whereas the strong association of current smoking with incident LC disappeared after adjustment for any of the 3 methylation markers. Here, AHRR is linked to laryngotracheoesophageal cleft.