OBJECTIVE, DESIGN, AND SUBJECTS: To examine the effects of nonoptimal birth condition on cortisol response to routine inoculation in a longitudinal sample of full-term healthy infants at 2, 4, and 6 months of age. Optimal versus non-optimal birth condition was defined by a large versus small head circumference and a high versus low 1-minute Apgar score. An optimal birth condition was associated with a high cortisol response at 2 months, but a low cortisol response by 6 months of age. The findings indicate a reversal in the meaning of high adrenocortical reactivity between 2 and 6 months of age: high cortisol response may index optimal functioning at 2 months, but nonoptimal functioning by 6 months of age. Together with other results, this reversal provides evidence for a developmental shift in adrenocortical functioning during this period. The findings also show that the effects of a nonoptimal birth condition in otherwise healthy full-term infants persist for at least the first 6 months of life.