Hepatocellular carcinoma (HCC) is usually preceded by cirrhosis whose genetic background is still poorly understood. The aim of this study was to evaluate, in non–end-stage cirrhosis, the fractional allelic loss (FAL) at loci mostly reported to be altered in HCC and the microsatellite instability (MSI). Twenty cases of cirrhosis were retrospectively selected. Eleven had developed an HCC during the follow-up (HCC-prone group), while 9 remained HCC-free (HCC-free group). Microdissected hepatocellular cirrhotic nodules from basal liver biopsies, were studied at 20 loci (on the chromosomal arms 1p and 1q, 3p, 4q, 6q, 7q, 8p, 13q, and 18q) and with the mononucleotide repeats BAT26andTGFbIIR. Genetic changes were detected in both groups. Overall, the FAL index was statistically increased in the HCC-prone group (0.213) as compared to the HCC-free group (0.094; P = .044). Allelic loss at chromosomal arms 1p, 4q, 13q, 18q, and concurrent losses at more than 3 loci were confined to the HCC-prone group. In both groups, MSI was never ascertained using BAT26and TGFbIIR. In conclusion, an increased FAL index and the lack of MSI characterize the non–end-stage cirrhosis of patients undergoing HCC during follow-up. These data emphasize the role of early clonal changes in chronic liver disease, and their potential predictive significance for clinical use.