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An extensive study of the epidemiological and serological characteristics of Mycoplasma pneumoniae infection was carried out in a military population. There was an increase in the infection rate at Camp Lejeune during the summer months as indicated by a relative increase in isolations, seroconversions, and hospitalizations for M. pneumoniae pneumonia. Twenty-three percent of the trainees who later became infected had detectable, pre-existing antilipid antibody to M. pneumoniae. When the whole organism was used as antigen, a pre-existing complement fixation (CF) titer of 1:4 or greater correlated with resistance to M. pneumoniae disease as defined by the absence of a fourfold rise in CF antibody, shedding of organisms, and clinical illness. Pre-existing antilipid fraction CF antibody titers of 1:16 or greater correlated with protection against mild and severe M. pneumoniae disease. Antilipid CF antibody titers of 1:4 and 1:8 were related to protection against mild disease but were not associated with protection against pneumonia which required hospitalization. The severity of illness was directly related to the CF antibody response in trainees with acute respiratory disease and pneumonia due to M. pneumoniae. The findings provide a basis for the development of a M. pneumoniae vaccine.