The present study was designed to investigate whether transsexuals can be validly subdivided into subtypes on the basis of sexual orientation, and whether differences between subtypes of transsexuals are similar for male-to-female (MF) and female-to-male transsexuals (FMs). Within a large transsexual sample (n = 187), homosexual and nonhomosexual subjects were compared on a number of characteristics before the start of treatment. Differences within MF and FM groups were also investigated. Homosexual transsexuals were found to be younger when applying for sex reassignment, reported a stronger cross-gender identity in childhood, had a more convincing cross-gender appearance, and functioned psychologically better than nonhomosexual transsexuals. Moreover, a lower percentage of the homosexual transsexuals reported being (or having been) married and sexually aroused while cross-dressing. The pattern of findings was different for MFs and FMs. No differences between homosexuals and nonhomosexuals were found in height, weight, or body mass index. A distinction between subtypes of transsexuals on the basis of sexual orientation seems theoretically and clinically meaningful. The results support the notion that in the two groups different factors influence the decision to apply for sex reassignment. The more vulnerable nonhomosexual transsexuals may particularly benefit from additional professional guidance before and/or during treatment.