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Objective The stromal cell-derived factor-1α/cysteine-X-cysteine chemokine receptor 4 (SDF-1α/CXCR4) axis promotes neuroprotection and angiogenesis in animal studies. Few studies have investigated the potential clinical implications of the SDF-1α/CXCR4 axis in patients with acute ischemic stroke (AIS). We evaluated the prognostic values of the SDF-1α/CXCR4 axis in patients with proximal middle cerebral artery occlusion. Methods Fifty-five patients and 18 age- and sex-matched volunteers were enrolled. Baseline clinical characteristics and risk factors of stroke were recorded. Peripheral whole blood cells were double stained with anti-CD34 and anti-CXCR4 (CD184). CD34+CXCR4+ cells were analyzed by flow cytometry. Plasma SDF-1α levels were measured by enzyme-linked immunosorbent assay. Results In the AIS group, plasma SDF-1α levels and the number of circulating CD34+CXCR4+ cells were significantly higher than those in controls. Day 1 SDF-1α levels were negatively correlated with infarct volume (r = −0.521) and the initial National Institutes of Health Stroke Scale score (r = −0.489). SDF-1α levels (day 1: r = −0.514; day 3: r = −0.275; day 7: r = −0.375) and circulating CD34+CXCR4+ cells (day 7: r = −0.282) were inversely associated with the 90-day modified Rankin Scale score. Conclusion The SDF-1α/CXCR4 axis has potential applications for predicting the clinical outcome of AIS.