A prospective study was conducted to identify and characterize hospitalizations for acute exacerbation of chronic obstructive pulmonary disease (AECOPD) with serologic evidence of infection with Mycoplasma pneumoniae (Mp). Two hundred forty hospitalizations for AECOPD were included in a 17-month prospective study. Paired sera were obtained for each of the hospitalizations and were tested serologically for Mp using a commercial enzyme immunoassay (EIA) kit. Only significant changes, according to the formula in the manufacturer's instructions, in antibody titers for IgM and/or IgG and/or IgA were considered diagnostic for Mp infection. In 34 hospitalizations (14.2%) the serologic tests for Mp were positive (MpH). In 29 of these hospitalizations (85%) a significant change in IgA was found. In 11 of these hospitalizations (32%) the only change identified was in IgA. In 24 MpH (71%) there was serologic evidence for infection with at least one other respiratory pathogen. In comparison to the 206 hospitalizations without serologic evidence of infection with Mp, MpH had higher rates of inhaled steroid therapy (41% vs. 24%, p = 0.033) and a longer time interval between the appearance of dyspnea and hospitalization (6.6 +/- 3.8 days vs. 5.0 +/- 3.5 days, p = 0.012). There were no significant differences between these two groups in a broad spectrum of patient- and exacerbation-related clinical variables. Specific antibiotic therapy for Mp in the MpH group did not shorten the hospital stay. Serologic evidence of Mp infection is common in patients hospitalized for AECOPD, and is usually based on changes in specific IgA antibody titers. In most MpH another respiratory pathogen can be identified. The vast majority of clinical characteristics are the same in patients with and without serologic evidence of infection with Mp. The practical implications of these findings should be clarified in further studies.