This study investigated the effect of storage parameters on the physicochemical changes of spray-dried infant milk formula (IMF) powders prepared with various lactose-to-maltodextrin (L:M) ratios (L:M 100:0, L:M 85:15 and L:M 70:30). Powders were characterized during 180 days of storage at 22 and 40 °C and relative humidity (RH) of 11, 23 and 54%. IMF powders were found mostly stable at both temperatures up to 23RH. Deteriorative physicochemical changes were observed at 54RH which were more rapid at 40 °C than at 22 °C. Increasing temperature and RH during storage decreased the glass transition temperature (Tg) to <0 °C and solubility to <25%, while crystallinity increased to >40%. Surface fat content, degree of aggregation and caking increased during storage. Increased surface fat was accompanied by a decrease in surface protein and carbohydrate contents. Incorporation of maltodextrin increased the Tg, decreased the crystallinity and improved the stability of powders.