This study assessed differences in quality of life (QL) between homosexual and heterosexual people and attempted to identify factors accounting for observed differences. Data were collected in a representative sample of the Dutch population aged 18-64 (N = 7,076). Classification as heterosexual or homosexual was based upon reported sexual behavior in the preceding year; 84.8% of the total sample (N = 5,998) could be classified: 2.8% of 2,878 sexually active men and 1.4% of 3,120 sexually active women had had same-sex partners. Differences in QL were tested by analysis of variance. Factors accounting for observed differences in QL were identified by selecting determinants of QL on which homosexual and heterosexual people differed and including them with same-sex sexuality in multiple regression analyses. Homosexual men, but not women, differed from their heterosexual counterparts on various dimensions of QL. Lesser QL in homosexual men was predominantly explained by self-esteem and mastery. Same-sex sexuality contributed independently to some of the observed differences. Although same-sex sexuality is related to QL in men, the lack of association in women suggests that the link is mediated by other factors, indicating the need to explore in what respect the situation of homosexual men and women differs. This study also suggests the importance of finding out how lower sense of self-esteem and of mastery come about in homosexual men.