We prospectively studied 91 infants born to women with systemic lupus erythematosus (SLE) or with SLE-like disease. Thirty-eight infants, including 3 sets of twins, were born to women who had anti-Ro, anti-La, or anti-RNP antibodies. Four infants had definite neonatal lupus, and 4 had possible neonatal lupus. No prospectively studied infant had congenital heart block. The presence of neonatal lupus did not correlate with the titer of anti-Ro antibodies. During the same time period, 2 additional babies with neonatal lupus and congenital heart block were born to mothers not previously known to have SLE. Taken together, these findings confirm the association of anti-Ro antibody with neonatal lupus, but indicate that life-threatening neonatal lupus is rare in children born to mothers who are known to have SLE, even when antibodies to Ro, La, or RNP are present. Prophylactic therapy is therefore not indicated for these women. An important proportion of mothers bearing children with neonatal lupus do not have recognized SLE and, currently, cannot be prospectively identified.