Objective To explore the expressions of serum procaspase activating compound-1 (PAC-1) and soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) in patients with acute ischemic stroke (AIS) and the relationship with prognosis. Methods 120 AIS patients admitted from January 2020 to January 2024 were included in AIS group, and 120 healthy volunteers who came to the hospital for physical examination during the same period were set as healthy group. The baseline data and expression levels of serum PAC-1 and sTWEAK were compared between groups. The correlation between serum PAC-1 and sTWEAK levels and clinical related data was analyzed. According to the modified RABKIN scale (mRS) score at 3 months after the onset of AIS, AIS patients were divided into excellent and good group (n=71) and poor group (n=49), and serum PAC-1 and sTWEAK expression levels were compared. The influencing factors affecting the prognosis of AIS patients were analyzed. ROC curve was drawn to analyze the diagnostic value of serum PAC-1 and sTWEAK levels on poor prognosis. Results The rates of hypertension, diabetes mellitus, history of hyperlipidemia, atrial fibrillation, coronary atherosclerosis, smoking and drinking and levels of WBC, fasting blood glucose, HbA1c, hs-CRP and IL-6 in AIS group were significantly higher than those in healthy group (P<0.05). The expression levels of serum PAC-1 and sTWEAK were significantly higher in AIS group than those in healthy group (P<0.05). Serum PAC-1 and sTWEAK expression levels were positively correlated with WBC, fasting blood glucose, HbA1c, hs-CRP and IL-6 (P<0.05). The expression levels of serum PAC-1 and sTWEAK in poor group were significantly higher compared with those in excellent and good group (P<0.05). The expression levels of serum PAC-1 and sTWEAK were correlated with the prognosis of patients (P<0.05). The AUCs of APAC-1 and sTWEAK in predicting poor prognosis were 0.857 and 0.694. The AUC of the combination of the two indicators was 0.884, and the combined diagnosis value was higher.Conclusion The expressions of serum PAC-1 and sTWEAK are correlated with the prognosis of AIS patients, and may be used as reference indicators