A guinea pig animal model of byssinosis has been described that demonstrates both acute and chronic effects of cotton dust inhalation (Ellakkani et al., 1984, 1987). During the latter study in which guinea pigs were exposed to 21 mg/m3 cotton dust 5 d/wk, 6 h/d for 52 wk, blood samples were taken from animals (20 exposed, 20 sham-exposed) prior to exposure and monthly during the exposure period. Sera were evaluated for quantities of the major protein fractions, and for IgG antibodies to cotton dust components. At the completion of the study, blood was evaluated for total and differential leukocytes. At 6 mo of exposure, each of the five protein fractions was significantly different from the corresponding fraction in the control animals. Antibodies reactive with an aqueous cotton dust extract (ACDE) were prominent by 2 mo of exposure and the titer was increased with continued exposure. The extract was composed of 2.6% protein, 12.8% reducing sugar, and 4.1% nucleic acid, with the remainder being largely simply sugars and inorganic material. A fraction of the antibodies showed reactivity with gram-negative bacteria and specifically with Enterobacter agglomerans, the most prevalent gram-negative microorganism in the dust. Minimal antibody response was detected using lipopolysaccharide from this microorganism or gram-positive bacteria. These results indicate that exposure of guinea pigs to cotton dust resulted in hematologic changes and in specific antibody formation. The presence of antibodies in each of the animals suggests their possible use as an indicator of cotton dust exposure.