Pathologic conditions associated with inflammation show an inverse correlation between high-density lipoprotein cholesterol (HDL-C) and inflammatory biomarker levels. Our aim was to investigate, in patients with acute coronary syndrome (ACS), whether very low HDL-C levels are associated with inflammatory biomarkers. In a cross-sectional study, we included 6,134 patients with ACS; they were classified as having very low (<30 mg/dl), low (30 to 39.9 mg/dl), and normal HDL-C (≥40 mg/dl) levels. We analyzed the association of different categories of HDL-C levels with serum levels of inflammatory biomarkers, high-sensitivity C-reactive protein (hs-CRP), albumin, and white blood cell count at admission. Overall, 18.5% of patients had very low HDL-C levels. Patients with very low HDL-C levels, compared to patients with low or normal HDL-C levels, had the highest hs-CRP (median 17.8 [interquartile range 7.2 to 54.5] vs 12.6 [5.6 to 33.9] vs 12.0 [5.4 to 36.9] mg/L, respectively, p <0.001) and the lowest albumin levels (median 3.6 [IQR 3.3 to 4.0] vs 3.8 [3.5 to 4.0] vs 3.8 [3.5 to 4.1] g/dl, respectively, p <0.001). White blood cell count did not differ significantly (p = 0.40). The multivariate analysis showed that albumin ≤3.5 g/dl (odds ratio 2.16, 95% confidence interval 1.88 to 2.49, p <0.001) and hs-CRP ≥10 mg/L (odds ratio 1.35, 95% confidence interval 1.17 to 1.55, p <0.001) were independent predictors of very low HDL-C levels. Patients with very low HDL-C levels had the highest inhospital mortality rates compared with the other groups. In conclusion, in patients with ACS, hs-CRP and serum albumin were associated independently with very low HDL-C levels.