We assayed fetal serum interferon-alpha (IFNA), a cytokine produced by leukocytes as a response to viral infection, in a series of 59 consecutive cases of ventriculomegaly diagnosed in utero and in 89 controls. Results were correlated with other findings including karyotype, maternal-fetal screening for serum antibodies to specific infectious pathogens, viral cultures of amniotic fluid, and neuropathological examination or postnatal follow-up. Fetal serum IFNA assay was negative in the five ventriculomegalies associated with a genetic anomaly and positive in the three cases with documented cytomegalovirus infections. In addition, fetal serum IFNA was detected significantly more often in the cases of ventriculomegaly with unexplained pathogenesis (15/51, 29.4 per cent) than in controls (1/89, 1.1 per cent). Detection of IFNA suggestive of viral infection in fetuses with otherwise unexplained ventriculomegaly underscores the need for more extensive viral screening in such cases.