The macrophage theory of depression proposes that an excessive secretion of monocyte/macrophage cytokines causes symptoms of depression. It has been suggested that changes in immune function that accompany pregnancy and childbirth could contribute to the affective symptoms suffered by many puerperal women. Tumour necrosis factor alpha (TNFalpha) is a pro-inflammatory cytokine that has been implicated in inflammatory infections and immune diseases. Production of TNFalpha has been shown to be regulated by oestrogen, which suggests it as a potential candidate for susceptibility to post-partum mood disorders. Several polymorphisms have been identified in the TNFalpha gene. The -308 promoter polymorphism has been associated with elevated production of TNFalpha and has been found to influence the neurological outcome of various infections. In a case-control association study, we have examined the frequency of this polymorphism in groups of parous DSM-IV Bipolar females with (N = 116) and without (N = 56) puerperal psychosis, and a female non-psychiatric comparison group (N = 72). We provided no support for the hypothesis that this polymorphism influences susceptibility to bipolar disorder, or acts as a trigger for puerperal psychosis. However, variation at other polymorphisms within TNFalpha or in other oestrogen-regulated genes involved in immune function remain interesting candidates for study in post-partum mood disorders.