The optimisation of the spray drying process for low-phenylalanine skim milk as a dietary supplement for phenylketonurics was studied. The effects of basic parameters including the inlet air temperature (100, 150 and 200 °C), feed flow rate (5, 10 and 15 mL min−1) and air flow rate (400, 600 and 800 L h−1) on the solubility and particle size of the low-phenylalanine skim milk powder were determined using response surface methodology. The optimum conditions have been obtained with inlet air temperature of 133 °C, feed flow rate of 5 mL min−1, and air flow rate of 800 L h−1. With the optimum parameters, the predicted values for the solubility and mean diameter were 95.33% and 5.34 μm, respectively, and experimentally were 94.36 ± 1.62% and 5.50 ± 0.44 μm, respectively. The experimental and predictive values were closely related showing predictive accuracy of the models.