Background The present study aimed to explore the association between RDW and CAS in patients with ischemic stroke, expecting to find a new and significant diagnosis index for clinical practice. Methods This cross-sectional study involves 432 consecutive patients with primary ischemic stroke (within 72 h). All subjects were confirmed by magnetic resonance imaging, and underwent physical examination, laboratory tests and carotid ultrasonography check. Finally, 392 patients were included according to the exclusion criteria. The odds ratios of independent variables were calculated using stepwise multiple logistic regression. Results Carotid intimal-medial thickness (IMT) and RDW are both significantly different between CAS group and control group. Univariate analyses show that high-sensitive C-reactive protein (Hs-CRP) and RDW ( r = 0.436) are both in significantly positive association with IMT. Stepwise multiple logistic regression shows that RDW is an independent protective factor of CAS in patients with ischemic stroke. Compared with the lowest quartile, the second to fourth quartiles are 1.13 (95% CI: 1.13–3.05), 2.02 (95% CI: 1.66–4.67), and 3.10 (95% CI: 2.46–7.65), respectively. Conclusion The present study suggested that RDW level were higher than non-CAS in patients with primary ischemic stroke. Our results facilitated a bridge to connect RDW with ischemic stroke and further confirmed the role of RDW in the progression of the ischemic stroke. [ABSTRACT FROM AUTHOR]