A number of studies have revealed significant relationships between cognitive performance and average phenylalanine (Phe) levels in children with phenylketonuria (PKU), but only a few studies have been conducted to examine the relationships between cognitive performance and variability (fluctuations) in Phe levels. In the current study, we examined a variety of indices of Phe control to determine which index best predicted IQ and executive abilities in 47 school-age children with early- and continuously-treated PKU. Indices of Phe control were mean Phe, the index of dietary control, change in Phe with age, and several indices of variability in Phe (standard deviation, standard error of estimate, and percentage of spikes). These indices were computed over the lifetime and during 3 developmental epochs (<5, 5.0-9.9, and ≥10 years of age). Results indicated that variability in Phe was generally a stronger predictor of cognitive performance than other indices of Phe control. In addition, executive performance was better predicted by variability in Phe during older than younger developmental epochs. These results indicate that variability in Phe should be carefully controlled to maximize cognitive outcomes and that Phe control should not be liberalized as children with PKU age.