The aim of the study was to determine the causes and prognostic implications of antimicrobial treatment failures in patients with nonresponding and progressive life-threatening, community-acquired pneumonia. Forty-nine patients hospitalized with a presumptive diagnosis of community-acquired pneumonia during a 16-mo period, failure to respond to antimicrobial treatment, and documented repeated microbial investigation >/= 72 h after initiation of in-hospital antimicrobial treatment were recorded. A definite etiology of treatment failure could be established in 32 of 49 (65%) patients, and nine additional patients (18%) had a probable etiology. Treatment failures were mainly infectious in origin and included primary, persistent, and nosocomial infections (n = 10 [19%], 13 [24%], and 11 [20%] of causes, respectively). Definite but not probable persistent infections were mostly due to microbial resistance to the administered initial empiric antimicrobial treatment. Nosocomial infections were particularly frequent in patients with progressive pneumonia. Definite persistent infections and nosocomial infections had the highest associated mortality rates (75 and 88%, respectively). Nosocomial pneumonia was the only cause of treatment failure independently associated with death in multivariate analysis (RR, 16.7; 95% CI, 1.4 to 194.9; p = 0.03). We conclude that the detection of microbial resistance and the diagnosis of nosocomial pneumonia are the two major challenges in hospitalized patients with community-acquired pneumonia who do not respond to initial antimicrobial treatment. In order to establish these potentially life-threatening etiologies, a regular microbial reinvestigation seems mandatory for all patients presenting with antimicrobial treatment failures.