Mean platelet volume (MPV) is suggested as an index of inflammation, disease activity, and anti-inflammatory treatment efficacy in chronic inflammatory disorders; however, the effect of MPV on sepsis mortality remains unclear. Therefore, we investigated whether the change in MPV between hospital admission and 72 hours (ΔMPV72h-adm) predicts 28-day mortality in severe sepsis and/or septic shock. We prospectively enrolled 345 patients admitted to the emergency department (ED) who received standardized resuscitation (early goal-directed therapy) for severe sepsis and/or septic shock between November 2007 and December 2011. Changes in platelet indices, including ΔMPV72h-adm, were compared between survivors and non-survivors by linear mixed model analysis. The prognostic value of ΔMPV72h-adm for 28-day mortality was ascertained by Cox proportional hazards model analysis. Thirty-five (10.1%) patients died within 28 days after ED admission. MPV increased significantly during the first 72 hours in non-survivors (P = 0.001) and survivors (P < 0.001); however, the rate of MPV increase was significantly higher in non-survivors (P = 0.003). Nonetheless, the difference in the platelet decline rate over the first 72 hours did not differ significantly between groups (P = 0.360). In multivariate analysis, ΔMPV72h-adm was an independent predictor of 28-day mortality, after adjusting for plausible confounders (hazard ratio, 1.44; 95% confidence interval, 1.01-2.06; P = 0.044). An increase in MPV during the first 72 hours of hospitalization is an independent risk factor for adverse clinical outcomes. Therefore, continuous monitoring of MPV may be useful to stratify mortality risk in patients with severe sepsis and/or septic shock.