Oral contraceptive (ORC)-related depression and irritability are among the most commonly reported drug-induced psychiatric symptoms. To investigate the etiological role of genetic factors in ORC-related symptoms, we studied questionnaire responses in 715 monozygotic and 416 dizygotic volunteer twin pairs concordant for ORC usage. Biometrical genetic analysis indicated that the liability to ORC-related depression was clearly influenced by genetic but not familial-environmental factors. Similar, but less definitive, results were found for ORC-related irritability. Multivariate genetic analysis indicated that both the genetic and the individual-specific environmental factors that influenced the liability to ORC-related depression and irritability were largely distinct from those that influence baseline levels of psychiatric symptoms. Genes play an important etiological role in ORC-related psychiatric side effects. The genes that influence liability to these side effects appear to differ from those that are etiologically important in baseline psychiatric symptomatology.