Background: As a classical biomarker associated with hypertension, the prognostic value of homocysteine (Hcy) in the intermediate-term outcome of acute coronary syndrome (ACS) remains controversial. This study aimed to investigate the role of homocysteine in ACS patients with different blood pressure statuses. Methods: A total of 1288 ACS patients from 11 general hospitals in Chengdu, China, from June 2015 to December 2019 were consecutively included in this observational study. The primary endpoint was defined as all-cause death. Secondary endpoints included cardiac death, nonfatal myocardial infarction (MI), unplanned revascularization and nonfatal stroke. The patients in the hypertension group (n = 788) were further stratified into hyperhomocysteinemia (H-Hcy, n = 245) and normal homocysteinaemia subgroups (N-Hcy, n = 543) around the cut-off value of 16.81 µmol/L. Similarly, the nonhypertensive patients were stratified into H-Hcy (n = 200) and N-Hcy subgroups (n = 300) around the optimal cut-off value of 14.00 µmol/L. The outcomes were compared between groups. Results: The median follow-up duration was 18 months. During this period, 78 (6.05%) deaths were recorded. Kaplan‒Meier curves illustrated that H-Hcy had a lower survival probability than N-Hcy in both hypertension and nonhypertension groups (p 0.01). Multivariate Cox regression analysis revealed that H-Hcy was a predictor of intermediate-term mortality in ACS, regardless of blood pressure status. Conclusions: Elevated Hcy levels predict intermediate-term all-cause mortality in ACS regardless of blood pressure status. This association could be conducive to risk stratification of ACS. Clinical Trial Registration: The study was registered in the Chinese Clinical Trials Registry in China (ChiCTR1900025138).