To establish whether there is any significant relationship between high-density lipoprotein cholesterol (HDLC) concentrations and biopsy-documented liver disease, 169 patients had needle biopsies, serum cholesterol, and HDLC evaluated. Twenty-four patients had serial cholesterol, HDLC, prothrombin, and aminotransferase levels and activities examined. In both men and women, HDLC decreased strikingly and significantly in acute alcoholic hepatitis and in acute viral hepatitis, compared to controls (p < 0.001). Men and women with inactive alcoholic liver disease and chronic active hepatitis showed moderate decreases in HDLC (p < 0.001). Patients with primary and metastatic hepatic neoplasms also had strikingly decreased HDLC (p < 0.001). Serial testing showed an excellent direct correlation between HDLC and prothrombin activity, r values ranging from 0.71 to 0.98. Although alcohol intake is known to correlate positively with HDLC concentrations, our data shows that this association is not absolute, and in most cases is reversed once liver disease becomes apparent.