Owing to dietary treatment, patients with phenylketonuria (PKU) are supplied with only small amounts of animal fats and show low blood cholesterol levels and a poor long-chain polyunsaturated fatty acid (LC-PUFA) status. Endogenous synthesis should compensate for the physiological need for cholesterol for growth, but supplementary exogenous LC-PUFA seems advisable. PKU infants could develop depletion of docosahexaenoic acid, fundamental for the functional development of the central nervous system. The availability of arachidonic acid from plasma in PKU has been found to be related to dietary compliance, and seems to influence the synthesis of arachidonate-derived eicosanoids. Trials of dietary supplementation of PKU patients with oils containing LC-PUFA are in progress, but the functional consequences of these supplementations need further investigation.