Our objective was to examine the permeability of the gut to protein macromolecules and sugar probes and their possible association in celiac disease patients. We studied the permeability to human alpha-lactalbumin, beta-lactoglobulin, mannitol, and lactulose on 46 occasions in 33 celiac disease patients in various phases of the disease; in addition, mannitol and lactulose permeability was studied in 18 healthy controls. Lactalbumin absorption was detected in 19 of 42 patients tested, more often in celiac disease patients with villous atrophy than in those with normal jejunal biopsy (p = 0.01). Higher absorption of lactalbumin was found in patients with subtotal villous atrophy than in those with normal biopsy (p = 0.02). beta-lactoglobulin was found in four of 42 patients tested. Less mannitol was absorbed by patients with either subtotal or partial villous atrophy than by those with normal histology (p = 0.001 and 0.006, respectively). Lactulose recovery was higher in newly diagnosed patients and patients with subtotal villous atrophy than in controls (p = 0.007 and 0.03, respectively). The lactulose/mannitol ratio was higher in newly diagnosed patients and patients with villous atrophy than in controls (p = 0.002 and 0.002, respectively). The correlation between permeability to lactalbumin and mannitol and lactulose was poor. We conclude that permeability to proteins and sugar molecules is abnormal in celiac disease patients with mucosal damage and that they probably reflect different mechanisms of penetration.