Facial pigmented spots are a common skin aging feature, but genetic predisposition has yet to be thoroughly investigated. We conducted a genome-wide association study (GWAS) for pigmented spots in 2844 Dutch Europeans from the Rotterdam Study (mean age: 66.9±8.0; 47% male). Using semi-automated image analysis of high resolution digital facial photographs, facial pigmented spots were quantified as the percentage of affected skin area (mean women: 2.0%±0.9, men: 0.9%±0.6). We identified genome-wide significant association with pigmented spots at 3 genetic loci: IRF4 (rs12203592, P=1.8 × 10(-27)), MC1R (compound heterozygosity score, P=2.3 × 10(-24)), and RALY/ASIP (rs6059655, P=1.9 × 10(-9)). Additionally, after adjustment for the other 3 top associated loci the BNC2 locus demonstrated significant association (rs62543565, P=2.3 × 10(-8)). The association signals observed at all four loci were successfully replicated (P<0.05) in an independent Dutch cohort (Leiden Longevity Study N=599). Although the four genes have previously been associated with skin color variation and skin cancer risk, all association signals remained highly significant (P<2 × 10(-8)) when conditioning the association analyses on skin color. We conclude that genetic variation in IRF4, MC1R, RALY/ASIP and BNC2 contribute to the acquired amount of facial pigmented spots during aging, through pathways independent of the basal melanin production.Journal of Investigative Dermatology accepted article preview online, 23 February 2015. doi:10.1038/jid.2015.62.