In phenylketonuria (PKU), compliance with taking protein substitute is an issue in teenage and older patients. A 'ready to drink' protein substitute may overcome many of the practical issues associated with its administration. Objective To investigate the efficacy of a liquid protein substitute in a 6-week, three-part, randomized, crossover, controlled study. Methods 27 subjects (15 female; 12 male) with PKU with a median age of 30 years (range 8-49 years) were recruited. One subject withdrew from the study. Their median daily dose of protein equivalent was 60 g (range 4575 g). In parts I and 2, subjects were randomized to either a liquid or a powder protein substitute with the same nutritional composition per unit (each 130 ml liquid pouch or 25 g powder sachet contained 15 g protein equivalent). In part 3, subjects chose liquid, powder or a combination of both. Weekly blood phenylalanine (Phe) concentrations were estimated, and during weeks 2, 4 and 6 subjects completed a daily questionnaire on administration issues. Results All but one of 26 subjects chose the liquid in part 3 as either their sole (69%, n = 18) or partial source (28%, n = 7) of protein substitute. Blood Phe concentrations were significantly better on the liquid (p = 0.03). With the liquid protein substitute, subjects were less self-consciousness (p = 0.003) and found it easier to take away from home (p = 0.001). Overall, the liquid was easier (p <0.0001), more convenient (p = 0.002) and resulted in less wastage of protein substitute (p <0.001). Conclusion Liquid protein substitute was popular and efficacious, reduced self-consciousness and overall improved compliance of teenagers and adults with PKU.