Children treated for phenylketonuria (PKU) have a low intake of whole animal foods. Consequently, the dietary intake of long-chain polyunsaturated fatty acids (PUFA) is just a few milligrams per day, mostly represented by arachidonic acid (AA). In a consecutive series of studies, we assessed in treated PKU children their long-chain PUFA status, the AA-related eicosanoid synthesis and the effects of specific PUFA supplementations. We found that the good compliance with the dietary regimen negatively influences the long-chain PUFA status and serum eicosanoid release from platelets. Supplementation with either marine or blackcurrant oils modifies the long-chain PUFA status of PKU children without approaching the fatty acid pattern of a healthy control population. Good-compliant PKU patients have diet-related, low levels of circulating long-chain PUFA, whose clinical and functional consequences deserve further investigation. The effects of dietary supplementations with long-chain PUFA of both the n-6 and n-3 series should be carefully evaluated.