ABSTRACT. To establish if intestinal permeability to exogenous antigens is involved in cow's milk allergy (CMA) in infants, 33 children 1 to 24 months old (18 controls and 1 5 with CMA) were tested for intestinal permeability to the protein marker horseradish peroxidase (HRP). Jejunal biopsies were performed either during the initial period of diagnosis, at the mean (and SE) age of 3 f 1 months, and/or 1 yr later, at the age of 13 f 2 months, just before and after a milk challenge. A small fragment of the biopsy was studied for histology and the remainder was mounted in an Ussing chamber for simultaneous measurement of mucosal to serosal transport of H R P in its intact and degraded forms and electrical parameters including short-circuit current and conductance. No modification in H R P absorption was noted in control children aged from 2 months to 11 yr, indicating that gut closure probably occurred earlier in life. During the initial period of CMA, transepithelial H R P fluxes were significantly higher, about 8-fold, in children with CMA (intact H R P flux = 48.5 f 15.2, 95% confidence interval, 11.2 to 85.7 versus 5.9 + 1.2, 95% confidence interval 2.9 to 8.3, in control children) In addition, short-circuit current was increased but conductance was unchanged. After several months on a milkfree diet, H R P flux and short-circuit current returned to control values. Just after the milk challenge and independently of -the clinical issue, a slight rise in H R P permeability was observed but it was not significant and remained within control values. These results suggest that increased permeability to proteins is probably not the primary cause of CMA, and that the increase in protein endocytosis noted during the initial period of CMA seems rather to be a secondary effect of an abnormal immunological response leading to mucosal inflammation and impairment of the endocytic process. (Pediatr Res 24:197-202, 1988)