The present study compared beta-lactam macrolide ("combination") therapy versus beta-lactam alone ("monotherapy") for hospitalised community-acquired pneumonia, using propensity scores to adjust for the differences between patients. A prospective multinational observational study was carried out. Baseline patient and infection characteristics were used to develop a propensity score for combination therapy. Patients were matched by the propensity score (three decimal point precision) and compared with 30-day mortality and hospital stay. The propensity score was used as a covariate in a logistic model for mortality. Patients treated with monotherapy (n = 169) were older (mean+/-sd age 70.6+/-17.3 versus 65.0+/-19.6 yrs), had a higher chronic diseases score and a different clinical presentation compared with patients treated with combination therapy (n = 282). Unadjusted mortality was significantly higher with monotherapy (37 (22%) out of 169 versus 21 (7%) out of 282). Only 27 patients in the monotherapy group could be matched to 27 patients in the combination group using the propensity score. The mortality in these groups was identical, with three (11%) demises each. The multivariable odds ratio for mortality associated with combination therapy, adjusted for the propensity score and the Pneumonia Severity Index, was 0.69 (95% confidence interval 0.32-1.48). The benefit of combination therapy versus monotherapy cannot be reliably assessed in observational studies, since the propensity to prescribe these regimens differs markedly.