Infants of diabetic mothers are thought to be at risk for perinatal asphyxia. We hypothesized that the following are significant risk factors for perinatal asphyxia: poor third-trimester glycemic control, diabetic vascular disease (nephropathy, retinopathy) appearing in pregnancy, pregnancy-associated hypertension, smoking, prematurity, fetal macrosomia, and maternal hyperglycemia and hypoglycemia within 6 hours preceding delivery. We prospectively studied 162 infants born to 149 diabetic mothers (White classes B through R-T). Perinatal asphyxia was defined clinically as fetal distress during labor (late decelerations, persistent fetal bradycardia, or both), 1-minute Apgar score less than or equal to 6, or intrauterine fetal death. Forty-four infants (26.7%) had perinatal asphyxia. The presence of perinatal asphyxia did not correlate with third-trimester glycemic control, pregnancy-associated hypertension, smoking, fetal macrosomia, or maternal hypoglycemia before delivery, but it did correlate significantly with nephropathy appearing in pregnancy, maternal hyperglycemia before delivery, and prematurity. We speculate that (1) the appearance of diabetic vasculopathy (nephropathy) during pregnancy is accompanied by placental vascular disease and subsequently by fetal compromise and (2) in pregnancy complicated by diabetes, maternal and subsequently fetal hyperglycemia before delivery leads to fetal hypoxemia.