Summary. Background: Platelet activation is implicated in thrombotic disorders, but has not been described in acute clinical pulmonary embolism (PE). Objectives: To investigate the natural history of platelet activation in PE and associated markers of inflammation, thrombosis and cardiac dysfunction. Methods: Thirty-five consecutive patients (age 62 ±17 years) with acute PE were prospectively enrolled and followed for 6 months. Platelet activation was assessed by flow cytometry [measuring expression of platelet P-selectin, conformational activation of glycoprotein IIb/IIIa complex (PAC-1) and formation of platelet–leukocyte complexes] and by plasma soluble P-selectin. Platelet activation, right ventricular (RV) function (assessed as RV ejection area by transthoracic echocardiography), D-dimer and high-sensitivity C-reactive protein (hs-CRP) were measured at presentation and repeated over 6 months follow-up. Results: Soluble P-selectin (56 ±19 ng mL−1, anovaP < 0.0001) and PAC-1 (1.5 ± 1.8%, anovaP = 0.005) were mildly but significantly increased in patients with acute PE relative to healthy young men (soluble P-selectin 33 ± 13 ng mL−1, P < 0.001; PAC-1 binding 0.5 ± 0.6%, P < 0.01) and age-matched controls (soluble P-selectin 31 ± 9 ng mL−1, P < 0.001; PAC-1 binding 0.4 ±0.4%, P < 0.05). Platelet P-selectin expression and platelet–leukocyte complexes were not increased during acute PE. Echocardiographic RV ejection area correlated inversely with soluble P-selectin (r = −0.47, P = 0.007) and positively with platelet P-selectin (r = 0.49, P = 0.0007), suggesting P-selectin is shed from activated platelets in proportion to the severity of RV dysfunction. Elevated soluble P-selectin, D-dimer and hs-CRP demonstrated a time-dependent return to normal during 6 months follow-up. Conclusion: Platelet activation is evident after acute PE. Platelet activation correlates with the severity of RV dysfunction, and can persist for several months after acute PE.