Background: Ischemic heart disease (IHD) is the leading cause of death and disability worldwide and in Iran, which imposes a heavy financial burden both on patient’s family and society. Objectives: This study aimed to analyze the direct medical costs of inpatients with IHD and its influencing factors in Iran in 2020. Methods: The sample of this cross-sectional study included 41,357 patients with IHD selected from the hospital information system (HIS) of the Iran Health Insurance Organization from August 23, 2019, to June 20, 2020. The study used the claims data of these patients, which included their demographics, length of stay (LOS), intensive care unit (ICU) admission, hospital accreditation grade, hospital ownership type, and patient discharge status. The multiple linear regression model was employed to evaluate the relationship between hospitalization costs and the associated factors. All statistical tests were conducted at the significance level of P < 0.05 using the R 3.6.3 software. Results: The mean age of patients was 63.95 ± 12.63 years old, and most of them were male (54.4%). The mean hospitalization cost per patient and per day was 586.42 ± 472.51 USD and 103.64 ± 100.29 USD, respectively. Moreover, the mean LOS was 4.92 days. Drugs and consumable medical supplies, as well as nursing and hoteling services, had the highest shares of hospitalization costs (29.54% and 29.4%, respectively). The hospitalization costs of patients with IHD were higher among men (β = 1.24), age 61 - 70 years (β = 1.38), LOS ≥ 5 (β = 2.92), ICU admission (β = 1.62), Iranian health fund (β = 1.21), and private hospitals (β = 1.91). Top-grade and first-grade hospitals had higher costs compared to grade 2 (β = 0.67), grade 3 (β = 0.35), and grade 4 (β = 0.72) hospitals. Deceased patients had also higher costs than patients with complete recovery (β = 0.63), relative recovery (β = 0.59), follow-up (β = 0.51), transfer to other medical centers (β = 0.44), and discharge against medical advice (DAMA) (β = 0.62). Conclusions: According to the results, shortening the LOS and controlling the high costs of drugs and consumable medical supplies are among the main strategies to reduce high hospitalization costs.