Streptococcus pneumoniae and Haemophilus influenzae are among the most common bacterial pathogens responsible for respiratory tract infections in otherwise healthy humans. Thirty-six strains of S. pneumoniae, 62 strains of H. influenzae, six hospitalacquired respiratory pathogens, and a strain of Streptococcus pyogenes were examined for production of IgA protease, a bacterial enzyme whose only known substrate is human IgA1. IgA protease was produced by 100% of the isolates of S. pneumoniae and 98% of the isolates of H. influenzae. The enzyme from both species cleaved human serum and secretory IgA1 proteins, but not human IgA2, IgG, or human serum albumin. None of the hospital-acquired pathogens had detectable IgA protease activity, a finding indicating that the production of this enzyme distinguishes S. pneumoniae and H. influenzae from the opportunistic respiratory pathogens.