Platelet distribution width (PDW), a marker of platelet size heterogeneity used as a readout of processes leading to platelet production and destruction, was recently reported to tag platelet activation variability. As platelets participate in the pathogenesis of many acute and chronic diseases, we evaluated PDW as a predictor of all-cause and cause-specific mortality. Longitudinal analysis was performed on 17,334 participants (52% women, mean age 55.6±12 years) in the Moli-sani study cohort, without a history of hematological diseases. Baseline PDW measurements were categorized in tertiles, the lowest acting as the reference. A multivariable Cox-proportional hazard model was used to estimate the association between PDW and mortality. Over a median follow-up of 11.6 years (interquartile range 10.7-12.5), 1,535 deaths [37.7% cardiovascular disease (CVD) and 36.5% cancer] were ascertained. As compared to those in the first PDW tertile (14.6-16.0 fL), individuals within the highest tertile (16.6-20.4 fL) had an increased risk of all-cause [hazard ratios (HR):1.20; 95% CI: 1.04-1.37] and CVD mortality (HR:1.29; 1.03-1.62). No association between PDW and cancer mortality was found in the whole sample. Subgroup analyses by two age classes (35-65y, ≥65y) showed that the association of PDW with both all-cause and cancer mortality was more apparent in the elderly (HR:1.34; 1.14-1.58, P for interaction =0.028 and HR:1.37; 1.01-1.85, P for interaction =0.020, respectively). We conclude that PDW-associated increase in CVD mortality risk could be related to accelerated/altered activation, production, or destruction of platelets, leading to several clinical conditions and death. In the elderly, PDW involvement in all-cause and cancer mortality should be further investigated. *Moli-sani investigatorsSteering committee: Licia Iacoviello, Giovanni de Gaetano, Maria Benedetta Donati. Scientific secretariat: Marialaura Bonaccio, Americo Bonanni, Chiara Cerletti, Simona Costanzo, Amalia De Curtis, Augusto Di Castelnuovo, Alessandro Gialluisi, Francesco Gianfagna, Mariarosaria Persichillo, Teresa Di Prospero. Safety and ethical committee: Jos Vermylen, Renzo Pegoraro, Antonio Spagnolo. External event adjudicating committee: Deodato Assanelli, Livia Rago. Baseline and follow-up data management: Simona Costanzo, Marco Olivieri, Teresa Panzera. Data analysis: Augusto Di Castelnuovo, Marialaura Bonaccio, Simona Costanzo, Simona Esposito, Alessandro Gialluisi, Francesco Gianfagna, Sabatino Orlandi, Emilia Ruggiero, Alfonsina Tirozzi. Biobank, molecular and genetic laboratory: Amalia De Curtis, Sara Magnacca, Fabrizia Noro, Alfonsina Tirozzi. Recruitment staff: Mariarosaria Persichillo, Francesca Bracone, Teresa Panzera. Communication and press office: Americo Bonanni. Regional institutions: Direzione Generale per la Salute - Regione Molise; Azienda Sanitaria Regionale del Molise; Agenzia Regionale per la Protezione Ambientale del Molise; Molise Dati Spa; Offices of vital statistics of the Molise region. Hospitals: Presidi Ospedalieri ASReM: Ospedale A. Cardarelli, Campobasso; Ospedale F. Veneziale, Isernia; Ospedale San Timoteo, Termoli (CB); Ospedale Ss. Rosario, Venafro (IS); Ospedale Vietri, Larino (CB); Ospedale San Francesco Caracciolo, Agnone (IS); Casa di Cura Villa Maria, Campobasso; Ospedale Gemelli Molise, Campobasso; IRCCS Neuromed, Pozzilli (IS), Italy.