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In the nematode Caenorhabditis elegans, nuclear hormone receptor DAF-12 regulates the decision to go into a resistant dauer diapause, in which the worm exhibits a decreased rate of aging. Using sequence similarity searches, we previously identified the liver X receptor alpha (LXR[alpha]) as one of the human nuclear hormone receptors the protein sequence of which is most similar to C. elegans DAF-12. Here, we studied whether variation in the gene encoding LXR[alpha] associates with human life span. In the Leiden 85-Plus Study, a population-based prospective follow-up study, we genotyped four polymorphisms spanning the gene coding for LXR[alpha] (NRIH3) and tagged four common haplotypes. Among 563 participants, haplotype 2 associated with reduced mortality during the 7-year follow-up (hazard ratio 0.78; p = .015), predominantly caused by reduced mortality from infectious disease (hazard ratio 0.31; p = .023). Haplotype 2 also associated with higher levels of plasma apolipoprotein E, a target gene of the LXR[alpha] (p = .018), and higher levels of triglycerides (p = .041). Genetic variation in the gene coding for the LXR[alpha] (NR1H3) associates with human life span.