The role of cow's milk in infantile colic in formula-fed infants was estimated in a double-blind study. Sixty colicky infants were given a cow's milk-containing formula (Enfamil) and a cow's milk-free formula based on soy (ProSobee). Eleven infants (18%) were free of symptoms while receiving soy formula. Symptoms of 32 infants (53%) were unchanged or worse when they were fed cow's milk formula and soy formula, but symptoms disappeared when they were fed a formula containing hydrolyzed casein (Nutramigen). Symptoms of 17 infants (29%) could not be related to the diet; these infants were permitted to continue on a cow's milk-based formula. A challenge with cow's milk-based formula after one month (at approximately age 3 months) produced symptoms of infantile colic in 22 infants (36%). At age 6 months, a challenge with cow's milk was positive in 11 infants (18%) with epidermal and gastrointestinal symptoms. Eight infants (13%) at 12 months of age and five infants (8%) at 16 months of age were still intolerant to cow's milk. Cow's milk seems to be a major cause of infantile colic in formula-fed infants. A dietary treatment is suggested for moderate or severe forms of the colic. Cow's milk protein intolerance is common later in infancy in these infants.