Background and Purpose CLEC-2 (C-type lectin-like receptor 2) is a C-type lectin receptor highly expressed on platelets with the prominent involvement in platelet activation, which was increased in coronary heart disease. Given the role of platelet activation in ischemic stroke and the connections between coronary heart disease and ischemic stroke, CLEC-2 might be a candidate marker of ischemic stroke. Here, we aimed to examine the prognostic significance of CLEC-2 in patients with acute ischemic stroke (AIS). Methods Three hundred fifty-two patients with AIS within 7 days and 112 healthy controls were prospectively studied. Plasma CLEC-2 (pCLEC-2) and some conventional risk factors of stroke were examined. Stroke progression was defined as any new neurological symptoms/signs or any neurological worsening within 7 days after stroke onset, and poor prognosis was defined as modified Rankin Scale scores >2 at 90 days. The association between pCLEC-2 and stroke progression/prognosis was evaluated using regression models. Results Patients with AIS had a significantly higher level of pCLEC-2 than that of healthy controls (P<0.05). Patients with AIS with progressive stroke or poor prognosis had a much higher level of pCLEC-2 compared with those with stable stroke or good prognosis (all P<0.05). Increasing pCLEC-2 was significantly associated with an increased risk of stroke progression (odds ratio, 1.97; 95% CI, 1.11-3.50; P=0.021) and poor prognosis (odds ratio, 1.70; 95% CI, 1.17-2.48; P=0.006). Patients with the highest pCLEC-2 level were 7- to 8-fold more likely to have stroke progression compared with the lowest quartile (odds ratio, 7.69; 95% CI, 1.43-41.41). Patients with the highest pCLEC-2 level were also more likely to have poor prognosis at 90 days (odds ratio, 5.58; 95% CI, 1.76-17.68). The optimal cutoff points of pCLEC-2 for predicting stroke progression and poor prognosis were 235.48 and 207.08 pg/mL, respectively. Conclusions Increased pCLEC-2 was associated with stroke progression and poor prognosis at 90 days significantly, which indicates the prognostic role of pCLEC-2 in AIS. However, it needs to be confirmed in large-scale studies.