Background: Platelet activity has an important role in the thrombotic mechanisms that occur following acute coronary syndrome (ACS) and acute ischemic stroke (AIS). Platelet size and activation status are inferred from mean platelet volume (MPV) and platelet distribution width (PDW), respectively, while platelet production via megakaryopoiesis involves the modulation by thrombopoietin (TPO). Objective: The purpose of this study was to evaluate the diagnostic value of serum TPO, platelet count, MPV and PDW in distinguishing AIS patients and ACS patients from normal subjects. Methods: A single center case-control study was performed on 25 AIS patients, 25 ACS patients and 20 healthy controls. Platelet indices and serum TPO was tested, followed by multivariable regression with adjustment for covariates (age, gender, hypertension, diabetes and smoking). The discriminative value of MPV, PDW and TPO were analyzed by receiver operating characteristic (ROC) curves. Results: MPV and PDW were significantly increased in both AIS and ACS than those of the control group (P < 0.01). Levels of serum TPO were significantly higher in AIS (129.0 ± 88.2 pg/mL) and ASC (179.4 ± 197.3 pg/mL) than in the controls (33.7 ± 7.9 pg/mL). Cases also had higher platelet counts. Receiver operating characteristic (ROC) analysis revealed that MPV had the greatest discriminatory power for AIS (area under the curve [AUC]: 0.834), and PDW was best for ACS (AUC: 0.783). Conclusion: The remarkable increase of MPV, PDW, and TPO in AIS and ACS provides evidences for them as promising diagnostic biomarkers that showed the increased platelet activation status and thrombopoietic activity. Larger quality-controlled multicenter studies are needed to confirm these findings and to investigate their prognosis implications.