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The impact of ICU-acquired pneumonia without etiologic diagnosis on patients’ outcomes is largely unknown. We compared the clinical characteristics, inflammatory response, and outcomes between patients with and without microbiologically confirmed ICU-acquired pneumonia.Prospective observational study.ICUs of a university teaching hospital.We prospectively collected 270 consecutive patients with ICU-acquired pneumonia. Patients were clustered according to positive or negative microbiologic results.None.We compared the characteristics and outcomes between both groups. Negative microbiology was found in 82 patients (30%). Both groups had similar baseline severity scores. Patients with negative microbiology presented more frequently chronic renal failure (15 [18%] vs 11 [6%]; p = 0.003), chronic heart disorders (35 [43%] vs 55 [29%]; p = 0.044), less frequently previous intubation (44 [54%] vs 135 [72%]; p = 0.006), more severe hypoxemia (PaO2/FIO2: 165 ± 73 mm Hg vs 199 ± 79 mm Hg; p = 0.001), and shorter ICU stay before the onset of pneumonia (5 ± 5 days vs 7 ± 9 days; p = 0.001) compared with patients with positive microbiology. The systemic inflammatory response was similar between both groups. Negative microbiology resulted in less changes of empiric treatment (33 [40%] vs 112 [60%]; p = 0.005) and shorter total duration of antimicrobials (13 ± 6 days vs 17 ± 12 days; p = 0.006) than positive microbiology. Following adjustment for potential confounders, patients with positive microbiology had higher hospital mortality (adjusted odds ratio 2.96, 95% confidence interval 1.24–7.04, p = 0.014) and lower 90-day survival (adjusted hazard ratio 0.50, 95% confidence interval 0.27–0.94, p = 0.031), with a nonsignificant lower 28-day survival.Although the possible influence of previous intubation in mortality of both groups is not completely discarded, negative microbiologic findings in clinically suspected ICU-acquired pneumonia are associated with less frequent previous intubation, shorter duration of antimicrobial treatment, and better survival. Future studies should corroborate the presence of pneumonia in patients with suspected ICU-acquired pneumonia and negative microbiology.