<b><i>Background and Purpose:</i></b> Poststroke fatigue (PSF) is a frequent and persistent problem in stroke survivors. The neuroanatomical model of PSF remains unclear. This study examined the association between PSF and cerebral microbleeds (CMBs). <b><i>Methods:</i></b> The sample comprised 199 patients with acute ischemic stroke. A psychiatrist who was blind to the subjects' radiological data administered the Chinese version of the Fatigue Severity Scale. PSF was defined as a Fatigue Severity Scale score of 4.0 or more. The locations of CMBs were evaluated with magnetic resonance imaging within 7 days of admission. <b><i>Results:</i></b> Of the 199 patients screened, 47 (23.6%) had PSF. The PSF group had a higher Geriatric Depression Scale score (p < 0.001) and a trend for a higher age (p = 0.074). The proportion of patients with deep CMBs was significantly higher in the PSF group (66.0 vs. 48.7%; p = 0.038). The presence of deep CMBs was a significant independent predictor of PSF with an odds ratio of 2.68 (p = 0.016). <b><i>Conclusion:</i></b> The results suggest that deep CMBs are associated with a higher risk of PSF. Further studies are needed to clarify whether CMBs affect the clinical presentation, treatment response and outcome of PSF.