A significant skewing in the sex ratio in favour of females has been reported for the families of homosexual men such that there are fewer maternal uncles than aunts. This finding is repeated for a large series of transsexual families in this study. Four hundred and seventeen male-to-female transsexuals and 96 female-to-male transsexuals were assessed. Male-to-female transsexuals have a significant excess of maternal aunts vs. uncles. No differences from the expected parity were found for female-to-male transsexuals or on the paternal side. A posited explanation for these findings invokes X inactivation and genes on the X chromosome that escape inactivation but may be imprinted. Our hypothesis incorporates the known familial traits in the families of homosexuals and transsexuals by way of retention of the grand parental epigenotype on the X chromosome. Generation one would be characterized by a failure to erase the paternal imprints on the paternal X chromosome. Daughters of this second generation would produce sons that are XpY and XmY. Since XpY expresses Xist, the X chromosome is silenced and half of the sons are lost at the earliest stages of pregnancy because of the normal requirement for paternal X expression in extra-embryonic tissues. Females survive by virtue of inheriting two X chromosomes, and therefore the possibility of X chromosome counting and choice during embryonic development. In generation three, sons inheriting the paternal X after its second passage through the female germline survive, but half would inherit the feminizing Xp imprinted genes. These genes could pre-dispose the sons to feminization and subsequent development of either homosexuality or transsexualism. Copyright 2000 Academic Press.