Introduction Chronic kidney disease (CKD) is one of risk factors for stroke and may be associated with impaired platelet reactivity. Objectives The aim of the study was to evaluate platelet reactivity in patients with CKD treated with acetylsalicylic acid (ASA), using 2 different laboratory methods. Moreover, we searched for factors responsible for the phenomenon of high on-treatment platelet reactivity (HOPR). Patients and methods A total of 108 patients with CKD and 41 controls without CKD using ASA were enrolled in the study. Platelet function was assessed by impedance aggregometry in whole blood, using a multi-channel platelet function analyzer (Multiplate®; ASPItest). Urinary 11-dehydrotromboxane levels were measured by the AspirinWorks® test. Results No significant differences were observed in the prevalence of HOPR between patients with and without CKD. Patients with CKD and HOPR measured by ASPItest had higher creatinine levels (P = 0.05) and were younger (P <0.01) than patients with CKD without HOPR, while patients with CKD and HOPR measured by AspirinWorks® had lower red blood cell count (P = 0.05), hemoglobin (P = 0.05), hematocrit (P = 0.05), and high-density lipoprotein levels (P = 0.05). All patients with HOPR had higher C-reactive protein levels (P <0.05) (AspirinWorks®) and white blood cells (P <0.05) (ASPItest). Conclusions The applied methods allowed to detect HOPR in more than one third of CKD patients taking ASA for stroke prevention. The compatibility of both methods for HOPR assessment was confirmed. The study revealed several potential risk factors for HOPR in CKD, including younger age, higher levels of inflammatory markers, dyslipidemia, and lower hematocrit and hemoglobin levels.