An infrequently encountered and poorly understood infantile disorder is gastrointestinal soy protein intolerance. Four patients who had intractable diarrhea of infancy and who failed to thrive were tested by oral challenge with soy protein isolate and were found to have soy protein intolerance. All four exhibited concomitant sensitivity to cow's milk protein. The response to challenge with soy protein included diarrhea, vomiting, hypotension, lethargy, and fever. These symptoms were immediate, of short duration, and occurred with each subsequent challenge dose. No patient exhibited cutaneous, pulmonary, or hematologic evidence of allergy although it was prominent in their families. A diet devoid of intact soy and cow's milk protein allowed symptomatic recovery and rapid weight gain. Oral disodium cromoglycate therapy was ineffective in one trial. Soy protein intolerance should be suspected in infants with diarrhea resistant to therapy with soy based formulas.