Acne is common and often leads to significant psychologic and physical morbidity. From clinical experience, acne appears to run in families; however, very few studies have investigated the genetic basis of this very common skin disease. A large twin study based on 458 pairs of monozygotic and 1099 pairs of dizygotic twins, all women with a mean age of 46 y was performed to investigate the relative contribution of genetic and environmental factors on the liability to acne. In addition, potential risk factors were assessed in twins with and without acne in a nested cross-sectional design. Fourteen percent of the twins reported a history of acne. Genetic modeling using acne scores showed that 81% (95% confidence interval 73-87%) of the variance of the disease was attributable to additive genetic effects. The remaining 19% was attributed to unique (i.e., unshared) environmental factors. Of the potential risk factors tested in 400 acne twins and 2414 unaffected twins, only apolipoprotein A1 serum levels were significantly lower in acne twins even after adjusting for age and weight. Family history of acne was also significantly associated with an increased risk. No significant differences were found between acne twins and nonacne twins for weight, body mass index, height, birth weight, hair thinning, reproductive factors as well as cholesterol, triglycerides, high-density lipoprotein, and glucose levels. The lower serum levels of apolipoprotein A1 in acne twins were also confirmed when analyzing acne discordant twin pairs. The evidence of a major genetic influence on acne should stimulate the search for potential genes that may lead to new therapeutic approaches.