This study evaluated the impact of cerebral microbleeds (CMBs) on the health-related quality of life (HRQoL) in 458 Chinese patients with first or recurrent acute ischemic stroke. HRQoL was assessed with the Short Form-36 (SF-36). Univariate analysis showed the presence of lobar CMBs to be negatively correlated with patients' physical functioning (PF; p < 0.01), social function (SF; p < 0.01), and role-emotional (RE; p < 0.05) scores. Subsequent linear regression analysis revealed lobar CMBs to be independently associated with the PF and SF scores (p < 0.05). The limitations of this study include the exclusion of patients with more severe stroke, the lack of longitudinal assessments, the use of a generic rather than stroke-specific HRQoL scale, and the less than optimal sensitivity of the CMB measurement. The study findings suggest that CMBs have a significant impact on the HRQoL of stroke survivors.