Background: Postnatal depression (PND) is associated with poor cognitive functioning in infancy and the early school years; long-term effects on academic outcome are not known. Method: Children of postnatally depressed (N = 50) and non-depressed mothers (N = 39), studied from infancy, were followed up at 16 years. We examined the effects on General Certificate of Secondary Education (GCSE) exam performance of maternal depression (postnatal and subsequent) and IQ, child sex and earlier cognitive development, and mother-child interactions, using structural equation modelling (SEM). Results: Boys, but not girls, of PND mothers had poorer GCSE results than control children. This was principally accounted for by effects on early child cognitive functioning, which showed strong continuity from infancy. PND had continuing negative effects on maternal interactions through childhood, and these also contributed to poorer GCSE performance. Neither chronic, nor recent, exposure to maternal depression had significant effects. Conclusions: The adverse effects of PND on male infants' cognitive functioning may persist through development. Continuing difficulties in mother-child interactions are also important, suggesting that both early intervention and continuing monitoring of mothers with PND may be warranted.