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Sepsis induces microvascular alterations that may play an important role in the development of organ dysfunction. However, the relationship of these alterations to systemic variables and outcome is still not well defined. We investigated which factors may influence microcirculatory alterations in patients with severe sepsis and whether these are independently associated with mortality.Analysis of prospectively collected data from previously published studies by our group.A 36-bed, medicosurgical university hospital Department of Intensive Care.A total of 252 patients with severe sepsis in whom the sublingual microcirculation was visualized using orthogonal polarization spectral or sidestream darkfield imaging techniques.Microcirculatory measurements were obtained either early, within 24h of the onset of severe sepsis (n = 204), or later, after 48h (n = 48). When multiple measurements were obtained, only the first was considered. Although global hemodynamic variables were relatively preserved (mean arterial pressure 70 [65–77] mm Hg, cardiac index 3.3 [2.7–4.0] L/min.m2, and SvO2 68.3 [62.8–74.7]%), microvascular variables were markedly altered (proportion of perfused small vessels 65 [50–74]%, microvascular flow index 2.15 [1.80–2.60], and heterogeneity of proportion of perfused small vessels 35 [20–50]%). Among microcirculatory variables, proportion of perfused small vessels was the strongest predictor of outcome (receiver operating characteristic curve area 0.818 [0.766–0.871], p < 0.001). Survival rates decreased markedly with severity of alterations in the proportion of perfused small vessels (70% and 75% in the two upper proportion of perfused small vessel quartiles compared with 3% and 44% in the two lower quartiles, p < 0.0001). Multivariable analysis identified proportion of perfused small vessels and sequential organ failure assessment score as independent predictors of outcome. Microcirculatory alterations were less severe in the later than in the earlier (proportion of perfused small vessels, 74 [57–82]% vs. 63 [48–71]%, p = 0.004) phase of sepsis. In multivariable analysis focused on the early period of sepsis, proportion of perfused small vessels and lactate were independent predictors of outcome.Microcirculatory alterations are stronger predictors of outcome than global hemodynamic variables.