For patients with community-acquired pneumonia (CAP), clinical response during the first days of treatment is predictive of clinical outcome. As risk assessments can improve the efficiency of pneumonia management, a prospective cohort study to assess clinical, biochemical and microbiological predictors of early clinical failure was conducted in patients with severe CAP (pneumonia severity index score of >90 or according to the American Thoracic Society definition). Failure was assessed at day 3 and was defined as death, a need for mechanical ventilation, respiratory rate >25/min, PaO2 <55 mm Hg, oxygen saturation <90%, haemodynamic instability, temperature >38 degrees C or confusion. Of 260 patients, 80 (31%) had early clinical failure, associated mainly with a respiratory rate >25/minute (n = 34), oxygen saturation <90% (n = 28) and confusion (n = 20). In multivariate logistic regression analysis, failure was associated independently with altered mental state (OR 3.19, 95% CI 1.75-5.80), arterial PaH <7.35 mm Hg (OR 4.29, 95% CI 1.53-12.05) and PaO2 <60 mm Hg (OR 1.75, 95% CI 0.97-3.15). A history of heart failure was associated inversely with clinical failure (OR 0.30, 95% CI 0.10-0.96). Patients who failed to respond had a higher 28-day mortality rate and a longer hospital stay. It was concluded that routine clinical and biochemical information can be used to predict early clinical failure in patients with severe CAP.