The objectives of this investigation were to study the temporal trends in hospitalizations of patients with sepsis in the Region of Madrid (Spain) from 2003 to 2011 and analyze the factors associated with inpatient mortality. All sepsis hospitalizations from the minimum basic data set (MBDS) during 2003 to 2011 in the Region of Madrid were analyzed. Genderspecific crude and age-adjusted rates were calculated each year. Factors associated with death in these patients were studied with bivariate and multivariate analyses. Simultaneously, sepsis inpatients also underwent descriptive analysis. The study included 98,898 sepsis episodes. The incidence of sepsis hospitalizations per 100,000 habitants increased in males from 114.4 in 2003 to 262.2 in 2011, and in females from 91.2 to 209.1 between 2003 and 2011. The observed inpatient mortality was 23.2 %. There were 45,936 (46.4 %) episodes of severe sepsis (≥1 organ failure), revealing a clear upward trend, especially in multi-organ failure. Severe sepsis mortality showed a decreasing trend in both males (40.0 to 31.8 % from 2003 through 2011) and females (41.6 to 35.2 % from 2003 through 2011). Death was most frequent among the elderly and in patients with more organ failures and comorbidities. In a populous region of Southern Europe, an upward trend in sepsis incidence was observed between 2003 and 2011, as well as a decreasing trend in mortality for sepsis inpatients. Mortality increased with age, comorbidities, and organ failures.