BACKGROUND AND PURPOSE: Acute ischemic stroke (AIS) is the most prevalent type of stroke, associated with a significant burden of functional impairments. About 94.2% of AIS patients present with multiple comorbidities, but how they affect AIS prognosis remains largely unknown. This study aims to comprehensively assess the associations of a wide range of AIS-related comorbidities, their patterns, with functional impairments in AIS patients. METHOD: This study utilized data from the China National Stroke Registry 3 (CNSR3), a prospective registry encompassing 201 Chinese hospitals from August 2015 to March 2018. A total of 10,508 AIS patients were included, with a median age of 62.0 years (IQR: 54.0-70.0), and 65% were female. Eighteen AIS-related comorbidities were considered in the analysis and frequent pattern mining was employed to identify potential comorbidity patterns among AIS patients. Functional outcomes at one year after an AIS event were assessed using the Modified Rankin Scale (mRS). Logistic regression models were utilized to evaluate associations of comorbidities, their patterns with AIS prognosis. Furthermore, association rule mining was applied to explore the hidden comorbidity combinations, and their relationship with functional outcomes based on the identified patterns. RESULTS: Comorbidity was observed in 88.9% of AIS patients. The majority of AIS patients exhibited one to three comorbidities. Eight patterns of main comorbidities among AIS patients were identified. The pattern of common metabolic disorders, coronary heart disease, and atrial fibrillation demonstrated the strongest association (OR = 2.49, 1.59 to 3.89) with the development of poor functional outcomes. The further combination of heart failure, and arthritis significantly increases the probability of poor functional outcomes, with lifts of 3.11 and 5.52, respectively. CONCLUSIONS: Our study revealed that comorbidity is highly prevalent among AIS patients in China, encompassing diverse patterns. Specific comorbidities and comorbidity patterns are closely associated with poor functional outcomes. Our findings emphasized the importance of prioritizing comprehensive management of AIS and AIS-related comorbidities to reduce the risk of disability among AIS patients.