A new amino acid formulation and a variety of treatment products incorporating it were evaluated for long-term safety, efficacy, and acceptance in 25 subjects with phenylketonuria over a period of 5 years. Palatability of the treatment was improved by reducing the required intake of amino acids, reformulating the mixture to have better taste, and providing vitamins and minerals as tablets. The hypotheses were that these strategies would improve compliance and metabolic control and maintain nutritional status in subjects. Compliance with treatment was determined from mean reported intakes (4-day diet records) and from mean 'received' intakes using receipts of treatment products actually shipped to individuals upon request. Mean amino acid intakes prescribed were significantly reduced from study entry to end, from 1.2 g/kg to 0.7 g/kg (p < 0.001). Reported intakes were similarly reduced from 1.3 g/kg to 0.7 g/kg (p < 0.001). While actually 'received' intakes of amino acid formula were also significantly reduced (p < 0.001), intakes by this measure were much lower than either prescribed or reported, 0.9 g/kg at entry and 0.4 g/kg at the end of the study, suggesting that acceptance of the treatment (usage of products), even when made more palatable, is below clinical expectations. In spite of these findings, mean serum proteins and minerals, height and weight were not significantly reduced during the study, supporting the safety of lowered intakes of amino acids and of nutritionally incomplete products. While the increase in mean serum phenylalanine concentration from 0.38 to 0.48 mmol/L was significant (p < 0.03), this mean rise of 0.1 mmol/L during a corresponding mean age increase of 4.2 years (from 6.9 to 11.1 years) is lower than in other recent reports from longitudinal studies of outcomes during this age range in subjects treated with traditional products. These data support the safety and efficacy of a more palatable and flexible approach to treatment.