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Although 28% to 49% of severe sepsis hospitalizations have been described as being "culture negative," there are very limited data on the epidemiology and outcomes of those with culture-negative severe sepsis (CNSS). The objectives of this study were to investigate the proportion and trends of CNSS and its association with mortality.Using the Nationwide Inpatient Sample (NIS) database from 2000 to 2010, we identified adults hospitalized with severe sepsis. Those without any specific organism codes were identified as "with CNSS." We examined the proportion of CNSS hospitalizations and rates of mortality associated with it. We also assessed the independent effect of CNSS on mortality.Of 6,843,279 admissions of patients with severe sepsis, 3,226,406 (47.1%) had culture-negative results. The age-adjusted proportion of CNSS increased from 33.9% in 2000 to 43.5% in 2010 (P .001). Those with CNSS had more comorbidities, acute organ dysfunction (respiratory, cardiac, hepatic, and renal dysfunction), and in-hospital mortality (34.6% vs 22.7%; P .001), although acute kidney injury requiring dialysis was less frequent (5.3% vs 6.1%; P .001). CNSS was an independent predictor of mortality in those with severe sepsis (OR, 1.75; 95% CI, 1.72-1.77).CNSS among hospitalized patients is common, and its proportion is on the rise. CNSS is associated with greater acute organ dysfunction and mortality. Having CNSS is an independent predictor of death.