We report a controlled study of intellectual outcome in 16 children with maple syrup urine disease (MSUD) that compares the outcome of MSUD diagnosed after symptoms became apparent with that of MSUD diagnosed prospectively and in unaffected siblings and parents. The mean IQ (±SD) score in the children with classic MSUD was 78±24; however, there were two discrete groups: one with normal IQ (>84) whose MSUD had been diagnosed at a mean age of 3.5 days and a second group, with IQ below normal, whose MSUD was diagnosed at a mean of 10 days of age. Affected children treated presymptomatically had higher IQ scores than their affected siblings treated when their disease was symptomatic. Multiple regression analysis indicated that the important influences on IQ were age at the time of diagnosis and long-term metabolic control; control at the time of testing also might have affected performance. The mean score of unaffected siblings was 92±5 and the mean parental IQ was 83±9. The mean IQ scores of children with variant MSUD, 97±4, was similar to that of their parents, 103±6. This study was not longitudinal and thus could not identify subtie developmental learning problems. We conclude that early and meticulous treatment of MSUD can result in intellectually normal children.