Antithrombotic agents are the mainstay for prevention of stroke in patients with atrial fibrillation (AF) and/or rheumatic heart disease (RHD). However, the impact of antithrombotic agents on cerebral microbleeds (CMBs) and leukoaraiosis remains controversial. We aimed to explore this association in Chinese ischemic stroke patients with AF and/or RHD. Ischemic stroke patients with AF and/or RHD within 7 days of onset from two hospitals were enrolled. Clinical information, prior use of antiplatelets or anticoagulation, presence and location of CMBs and leukoaraiosis were recorded. Totally, 160 patients (median age, 71 years) were included. CMBs were observed in 90 (56.3%) patients, of whom 37 were with strictly lobar CMBs and 53 were with deep/infratentorial CMBs. leukoaraiosis was observed in 107 (66.9%) patients. There was a significant difference in antiplatelet use between patients with and without CMBs (33.3 vs. 11.4%, P = 0.001), but not found for anticoagulants. Prior use of antiplatelets was independently associated with the presence of CMBs (OR 3.075, 95% CI 1.175–8.045, P = 0.022) and especially strictly lobar CMBs (OR 2.635, 95% CI 1.050–6.612, P = 0.039) in multivariate analysis. However, no significant association was found between any antithrombotic agent and leukoaraiosis. CMBs and leukoaraiosis are common cerebral small vessel disease markers in ischemic stroke patients with AF and/or RHD. Prior antiplatelet use is independently associated with the presence of CMBs predominantly in the strictly lobar region.