To determine the impact of initial antimicrobial choice on 30-day mortality rate in patients with community-acquired pneumonia due to Streptococcus pneumoniae (CAP-SP), a prospective, observational study was conducted in 35 Spanish hospitals. A total of 638 patients with CAP-SP were identified. Antimicrobials were chosen by the attending physician. Patients were grouped into the following categories: beta-lactam monotherapy (n = 251), macrolide monotherapy (n = 37), beta-lactam plus macrolide (n = 198), levofloxacin alone/combination (n = 48), and other combinations (n = 104). The reference category was beta-lactam+macrolide. The 30-day survival probability was 84.9%. Using multivariate survival analysis, factors related to mortality in the entire population were: bilateral disease, suspected aspiration, shock, HIV infection, renal failure and pneumonia severity index (PSI) score Class IV versus I-III and categories V versus I-III. The association of beta-lactams+macrolides was not better than the use of beta-lactams alone. The current authors analysed the different groups of patients with significant mortality/morbidity: intensive care unit, PSI Class >III, renal failure, chronic lung disease and bacteraemia. Only in patients with PSI Class >III, who had undergone initial antimicrobial choice classified as other combinations, were associated with higher mortality. In conclusion, the current authors have not demonstrated an independent association between initial antimicrobial regimen and 30-day mortality in community-acquired pneumococcal pneumonia patients, except for those with a higher pneumonia severity index score.