Prospective studies have suggested that some individuals have a persistent IgM response to Mycoplasma pneumoniae infection with relatively little IgG production over many months. Persistence of the organism in patients with an allergic phenotype might predispose to the development of asthma. This study was designed to analyze the prevalence of M. pneumoniae infection and the immune response to that infection among children with asthma compared with controls. A prospective study was performed in 82 children with physician-diagnosed asthma and 98 nonasthmatic controls over a 5-year period comparing them for evidence of current or prior infection by M. pneumoniae using serology (IgG and IgM), culture, and polymerase chain reaction (PCR), and in vitro cellular responses to M. pneumoniae antigen. Similar numbers of controls (9/98) and asthmatic children (6/82) were PCR+ for M. pneumoniae at some time during the study. IgM antibody to M. pneumoniae was detected in similar numbers of controls (21/98) and asthmatic children (18/82), but positive IgG antibody titers were detected in significantly more controls (13/98) than asthmatic children (3/82; p = 0.03). Similar numbers from each group were IgM+ on more than one annual visit (9/98 controls and 7/82 asthmatic children). Antigen-driven proliferation and interferon (IFN) gamma production by mononuclear cells from IgM+ controls were significantly greater than that of IgM- controls, but there was no difference in proliferation and IFN-gamma production by cells from IgM+ and IgM- asthmatic children. These results suggest that asthmatic children have deficient cellular and humoral responses to M. pneumoniae infection compared with nonasthmatic controls. Copyright © 2009, OceanSide Publications, Inc.