Oxidative stress and inflammation are central in the pathophysiology of light-chain amyloid cardiomyopathy (AL-CM). High-density lipoprotein cholesterol (HDLC) is an antioxidant and acts as an anti-inflammatory regulator. In this study, the prognostic value of serum HDL-C was explored in AL-CM. In this prospective single-center study, two hundred consecutive patients with biopsy-confirmed light-chain amyloidosis (AL) and cardiac involvement were enrolled. Patients were classified into low or normal serum HDL-C groups (HDL-C < 40 mg/dL and HDL-C ≥ 40 mg/dL, respectively). Univariate and multivariate Cox models were used to identify predictors of survival. Kaplan-Meier analysis was performed to compare survival between patients with low or normal serum HDL-C. Patients with low serum HDL-C were more likely to present with higher levels of cardiac troponin-T (123.4 ng/L vs. 79.1 ng/L, p = 0.026) and higher levels of N-terminal pro-B-type natriuretic peptide (9146 pg/mL vs. 4945 pg/mL, p = 0.011). Patients were followed for a median follow-up period of 19 months, in which 118 (59%) patients died. The median overall survival times for patients with low or normal serum HDL-C were 7 and 16 months, respectively (p = 0.002). Multivariate analysis demonstrated that serum HDL-C (HR 0.984, 95% CI 0.973-0.994, p = 0.003) was independently associated with prognosis, after adjusting for nephrotic syndrome, hepatic involvement, nutritional state, renal function, SBP, DBP, serum uric acid, total cholesterol, Mayo AL 2004 stage, and treatment with chemotherapy. HDL-C is a novel serum biomarker for disease severity and prognosis in light-chain cardiac amyloidosis. Copyright © 2020 Elsevier B.V. All rights reserved.