Background. Low birth-weight (LBW) infants have a high incidence of serious infections. These are difficult to diagnose early. Thus, prophylactic treatment with antibiotics appears to be rational, but the best choice of antibiotics is uncertain.Objective. In newborn LBW infants, to compare the effects on death rate and principal findings at necropsy of two prophylactic antibacterial regimens, oxytetracycline (OT) versus penicillin/sulfisoxazole (P/S).Methods. Consecutively admitted LBW infants (N = 193) were randomly assigned, within three birth-weight strata, to receive either subcutaneous 0T or a combination of P/S. The primary outcomes were death before 120 hours, death before 28 days, and principal diagnoses at necropsy.Results. Infants allocated to P/S had a large and statistically significant increase in death rate, determined up to 120 hours (OT, 20.6%; P/S, 48.4%; absolute risk increase, 27.8%) and up to 28 days (0T, 27.8%; P/S, 63.2%; absolute risk increase, 35.3%). This increase in deaths was not attributable to death from infection; the incidence of positive postmortem blood culture results was lower in the P/S group, and there was no significant difference between groups in the incidence of pneumonia or other infections at necropsy. However, in the P/S group, there was a large, unexpected, and statistically significant increase in the finding of kernicterus at necropsy among necropsied deaths occurring up to 120 hours (0T, 6.3%; P/S 36.4%; absolute risk increase 30.1%) and up to 28 days (0T, 4.5%; P/S, 43.2%; absolute risk increase, 38.7%).Conclusions. Infants who received P/S died at a significantly higher rate and had a higher rate of kernicterus at necropsy than those who received OT. The mechanism of the differences observed in rates of mortality and death with kernicterus is unknown.