Ten Haemophilus somnus isolates were grown on blood agar plates under a 5% CO2 atmosphere for 48 h. Harvested whole cells were washed and evaluated for the presence of histamine by ELISA. All H. somnus isolates had cell-associated histamine concentrations of between 18.5 and 200 ng/ml. In a separate study, the ability of H. somnus to secrete histamine into BHI growth medium was evaluated using H. somnus strains 8025 and 156A as well as a recent 156A respiratory isolate. Each strain or isolate was grown under various concentrations of CO2 to approximate the CO2 concentration in the bronchi. The histamine content of washed whole cells and medium supernatant were determined at various stages of incubation. Highest histamine concentrations were detected in the recent respiratory isolate; whole cells (225 ng/ml) after 120 h incubation in 15% CO2 and supernatant (1721 ng/ml) after incubation for 41 h in 25% CO2. This study indicates that different H. somnus isolates can produce and secrete histamine which may be enhanced by CO2 concentrations which approximate those in the bronchial tree. Results of this study may partially explain some of the post-vaccination reactions occasionally observed with H. somnus bacterins. Additional studies are needed to determine the actual role of H. somnus-derived histamine in the pathogenesis of bovine respiratory disease and airway hyperresponsiveness.