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Ganoderma lucidum is a type of mushroom that has been used for thousand years throughout Asia. It is known to demonstrate numerous health benefiting properties including antioxidant, anti-inflammation, anticancer effects, hypoglycemic and blood cholesterol reducing properties. This research was conducted to determine the efficacy of Ganoderma lucidum polysaccharide peptides (PSP) as anti-inflammation and antioxidant in cardiovascular disease.This is a true experimental study with pre- and post-test design of 37high-risk patients of cardiovascular disease based on the Framingham Risk Score that was conducted for 3 months. They were advised to consume PSP 3x250 mg as adjuvant to their previous medications, and they did some examination. Statistical analysis was conducted using paired t-test for parametric data and Wilcoxon test for non-parametric data.From 37 patients we found that the administration of PSP 3x250 mg could reduce total cholesterol level by 3.48 ± 46.9 mg/dl (p = 0.672). Both pre- and post-test of total cholesterol are significantly correlated (r = 0.618, p = 0.000). PSP administration, however, increased HDL cholesterol levels by 7.84 ± 10.79 (p = 0.000). The systolic blood pressure decreased from 130.14 ± 43.37 mmHg to 118.24 ± 55.68 (p = 0.109), and the diastolic blood pressure decreased from 80 ± 25.74 mmHg to 73.24 ± 33.85 mmHg (p = 0.102). Despite a great reduction of blood pressure to normal range, it was not statistically significant. The reduction of anti-inflammatory markers interleukin-6, from 279.75 ± 120.76 to 29.32 ± 26.44 (p = 0.000) and TNF alpha, from 13447.84 ± 2199.46 to 544.85 ± 292.06 (p = 0.000) were significant. Malondialdehyde (MDA) level also decreased significantly with PSP for 3 months (114.13 ± 24.56 to 36.84 ± 28.39, p = 0.000).The administration of polysaccharide peptides Ganoderma lucidum for three months in high-risk patients with hypertension can reduce the blood pressure within normal range, improve total cholesterol level and significantly play role as anti-inflammation and antioxidant in cardiovascular disease.