Abstract Background Platelet activation and consumption are common in critically ill patients and are associated with poorer prognosis. Mean platelet volume is a simple surrogate for platelet activation, with higher MPV being associated with worse clinical condition on a large array of clinical diagnoses. We therefore aimed to investigate associations between changes in platelet count and mean platelet volume (MPV) with prognosis and inflammatory cytokine values in critically ill patients. Methods This study prospectively included 84 critically ill patients. Patients were stratified into four groups according to proportional changes in MPV (ΔMPV 24h ) and platelet count (ΔPlat 24h ) in the first 24 hours after admission. Mortality between groups was compared using the χ 2 test. Logistic regression was performed using hospital mortality as outcome and Simplified Acute Physiology Score (SAPS 3), ΔPlat 24h and ΔMPV 24h as covariates. Concentrations of the following inflammatory mediators were measured using Miliplex® technology: IL1β, IL6, IL8, IL10, epidermal growth factor, vascular endothelial growth factor, TNFα and IFNα. Cytokine concentrations were compared between groups using the Kruskal-Wallis test with Bonferroni correction. Results Patients in whom MPV increased and platelet count decreased had higher mortality rates (46%). According to logistic regression, ΔMPV 24h was independently associated with increased mortality (OR 1.28 per 1% increase; 95% CI 1.08 to 1.48). No strong associations between inflammatory mediators and changes in MPV and platelet count were found. Conclusion An increase in MPV after admission to an ICU is independently associated with higher hospital mortality.