The purpose of this study was to determine if a group of patients with unexplained second or third trimester fetal demise have an increased prevalence of antinuclear antibodies (ANA) when compared to controls. During a 5-year period from January 1989 through December 1993, the records of all fetal deaths > or = 500 g or > or = 20 weeks of gestation that occurred at our institution were reviewed. In these women the ANA titers were checked at the discretion of the physician. The proportion of positive ANA tests in the group of women with explained fetal deaths was compared to that in women with unexplained fetal deaths. These results were then compared to a control group of healthy gravidas presenting to labor and delivery in the third trimester. During this time period, 848 fetal deaths were recorded. Our study population consisted of 286 patients who had an unexplained second or third trimester fetal demise with a record of having an ANA drawn. Of the 376 explained fetal deaths, 190 had an ANA assayed. The control group included 299 healthy third trimester gravidas. In the group of patients with unexplained fetal death, 11.5% (33/286) had a positive ANA, whereas 16% (31/190) of ANA tests were positive in cases of explained fetal death (P = 0.17). In the control group, 14% (43/299) had a positive ANA. There were three distinct immunofluorescence patterns: nucleolar, speckled, and homogeneous. The first two were seen more often in the control group, whereas the latter was seen more frequently in those patients with fetal death (P = 0.10). The incidence of a significant circulating ANA titer was similar in patients and controls. Moreover, there was no significant association between circulating antinuclear antibody titers and fetal outcome. More patients with a fetal death had a homogeneous nuclear fluorescence pattern when compared to controls; however, this finding was not statistically significant. Therefore, we do not recommend routine testing for ANA in women with unexplained second or third trimester fetal death.