Although a number of studies have shown that various measures of religiosity are inversely correlated with smoking behavior, none of these studies have used genetically informative samples to test for a gene-environment interaction between the determinants of smoking initiation and religiosity. We tested the moderating effects of three measures of religiosity (religious affiliation, organizational religious activity, and self-rated religiousness) on the genetic and environmental determinants of smoking initiation in 237 monozygotic twin pairs, 315 dizygotic twin pairs, 779 full-sibling pairs, and 233 half-sibling pairs in young adults surveyed from the third wave of the National Longitudinal Study of Adolescent Health. Primary analyses incorporated all sibling pairs, irrespective of whether they were concordant or discordant for the environmental moderator, in models designed to account for the confounding effects of a gene-environment correlation. High levels of self-rated religiousness attenuated the additive genetic component for smoking initiation and were associated with a lower prevalence of smoking initiation. Although all three measures of religiosity were associated with lower rates of smoking initiation, only self-rated religiousness moderated genetic influences on the liability for smoking.