Numerous mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR, a Cl(-) channel) disrupt salt and fluid transport and lead to the formation of thick mucus in patients' airways. Obstruction by mucus predisposes CF patients to chronic infections and inflammation, which become gradually harder to control and eventually fatal. Aggressive antibiotic therapy and supportive measures have dramatically lengthened CF patients' lives. Here, we report that sphingomyelinases (SMase) from human respiratory pathogens strongly inhibit CFTR function. The hydrolysis of sphingomyelin by SMase makes it more difficult to activate CFTR by phosphorylation of its regulatory domain. By inhibiting CFTR currents, SMase-producing respiratory tract bacteria may not only aggravate pulmonary infection in some CF patients but may also elicit a condition, analogous to CFTR deficiency, in non-CF patients suffering from bacterial lung infection.