Non-right-handedness appears to be more common among bisexuals and homosexuals than among heterosexuals, which might be indirect evidence of effects of prenatal androgen exposure. Current data suggest higher prenatal testosterone levels among bisexual and homosexual women, but are inconclusive for men. This study examined the association between sexual orientation and non-right-handedness for sex differences and whether higher rates of mixed-handedness, rather than left-handedness, might be the driving factor. This allowed for more specific tests regarding the predictions of two competing theories of prenatal androgen exposure, the Geschwind–Galaburda theory and the callosal hypothesis, than in previous research. Being a potentially better indicator of cerebral lateralization than handedness, associations with footedness were also explored. To counter inconsistencies and shortcomings of previous research, we utilized two large discovery and replication datasets (ns = 2368 and 1565) and applied latent variable analysis to reliably classify lateral preferences (i.e., handedness, footedness). This maximized the statistical conclusion validity and allowed for direct tests of replicability. Sexual orientation was differentially associated with lateral preferences among men and women. Associations among women were consistent with predictions of the Geschwind–Galaburda theory, whereas among men they were consistent with predictions of the callosal hypothesis. The results were further consistent with models of homosexuality that suggest a role of parental epigenetic marks on sexually dimorphic fetal development. Research efforts should be increased with regard to footedness and epigenetic theories of homosexuality.