The ability of an Actinobacillus pleuropneumoniae serotype 2 strain to associate in vivo with the epithelium of the porcine respiratory tract was investigated in a sequential study after intranasal inoculation of hysterectomy-derived and colostrum-deprived pigs. At 30 min postinoculation more than 95% of the bacteria present in the lungs were intimately associated with the epithelium of the alveoli or the cilia of the terminal bronchioli, as observed by light and electron microscopy. At 90 and 180 min postinoculation multiple focal early inflammatory lesions in which histologically different, more or less concentric zones could be distinguished were observed. In the center of these pneumonic areas bacteria were associated with infiltrated cells and exudate. In the zone surrounding the center, approximately 95% of the bacteria were lying with their longest side in close apposition to the epithelial cells of alveoli and the cilia of the terminal bronchioli. Bacteria were only sporadically associated with the cilia or the epithelium of the bronchi and trachea. Bacteria were not observed in tonsils or conchae. In view of the findings presented here, we propose the hypothesis that adherence of the A. pleuropneumoniae serotype 2 strain to epithelial cells of the lower respiratory tract constitutes an important initial step in pathogenesis.