Variability of metabolic control in phenylketonuria (PKU) potentially affects cognitive outcome in early and continuously treated children with this condition. The possibility that homeostasis is more important than the absolute level of exposure to phenylalanine (phe) has not previously been examined. A meta-analysis of 40 studies showed that in children with phenylketonuria (PKU), mean lifetime blood phe levels were significantly correlated with Full Scale IQ (FSIQ) (r=-0.34). A similar correlation (r=-0.35) was found between FSIQ and mean exposure during 0-12 years of age. Most of the studies in the meta-analysis, however, included children who had discontinued the phe restricted diet. None examined the impact of fluctuations in metabolic control in continuously treated children. This is important because new therapies may increase stability in blood phe levels. The question has arisen whether these therapies are beneficial in children whose blood phe levels are generally within the recommended range of 120-360 micromol/L. In this study, we describe the relationship between FSIQ and two parameters of metabolic control: (1) mean blood phe level of all reported specimens for each subject, and (2) variability of the blood phe level as indicated by the standard deviation of blood phe levels for each subject. Analyses were performed using lifetime phe levels and levels during three periods (0-6 years, 0-10 years, and >10 years of age). The most recent FSIQ for each child was used in the correlation analyses. Data were collected from medical records on all 46 children born between 1999 and 2006 with early and continuously treated PKU followed at the Metabolism Program at Children's Hospital Boston. The mean age of the children at the time of their most recent FSIQ test was 7.5+3.3 (2.9-15.5) and their mean FSIQ was 104+15 (68-143). The mean lifetime blood phe level in these children was 312+132 micromol/L (125-852). The standard deviation of blood phe levels was 182+72 micromol/L (96-336). The correlation between lifetime blood phe levels and most recent FSIQ was -.17 (p=0.38) and the correlation between standard deviation of blood phe levels and most recent FSIQ was -.36 (p=.058), not reaching significance, but indicating a trend. These results indicate that stability of blood phe levels may be more important to cognitive functioning than overall exposure to phe in early and continuously treated PKU. In treating PKU, attention should be given to variability in blood phe levels as well as maintenance of phe levels within the recommended range.