Previous studies showed that C-reactive protein (CRP), an inflammatory marker, was associated with stroke severity and long-term outcome. However, the relationship between the acute-phase CRP level and discharge outcome has received little attention. We prospectively studied 301 patients with acute ischemic stroke (over a period of two weeks) from two hospital stroke wards and one rehabilitation department in Henan, China. Patients’ demographic and clinical data were collected and evaluated at admission. Poor discharge outcome was assessed in patients at discharge using the Modified Rankin Scale (MRS > 2). Multivariate logistic regression analysis was performed to determine the risk factors of poor discharge outcome after adjusting for potential confounders. Poor discharge outcome was observed in 78 patients (25.9%). Univariate analyses showed that factors significantly influencing poor discharge outcome were age, residence, recurrent acute ischemic stroke, coronary heart disease, the National Institutes of Health Stroke Scale (NIHSS) score at admission, non-lacunar stroke, time from onset of stroke to admission, CRP, TBIL (total bilirubin), direct bilirubin (DBIL), ALB (albumin), FIB (fibrinogen) and D-dimer (p < 0.05). After adjusting for age, residence, recurrent ischemic stroke, coronary heart disease, NIHSS score at admission, lacunar stroke, time from onset of stroke to admission, CRP, TBIL, DBIL, ALB, FIB and D-dimer, multivariate logistic regression analyses revealed that poor outcome at discharge was associated with recurrent acute ischemic stroke (OR, 2.115; 95% CI, 1.094–4.087), non-lacunar stroke (OR, 2.943; 95% CI, 1.436–6.032), DBIL (OR, 1.795; 95% CI, 1.311–2.458), and CRP (OR, 4.890; 95% CI, 3.063–7.808). In conclusion, the CRP level measured at admission was found to be an independent predictor of poor outcome at discharge. Recurrent acute ischemic stroke, non-lacunar stroke and DBIL were also significantly associated with discharge outcome in acute ischemic stroke.