More than one fifth of the world's population suffers from liver cirrhosis or other chronic liver diseases. Unfortunately, some of them will inevitably develop hepatocellular carcinoma (HCC), due to the vast majority of HCC cases arising against the background of liver cirrhosis. Despite this clearly identified high-risk group, the lack of early diagnostic options causes HCC mortality to approach its incidence. As opposed to many types of cancer, the incidence of HCC is expected to grow in the coming decades, which makes the search for an effective early diagnostic option a pressing necessity. This study presents evidence that blood plasma analysis employing a combination of chiroptical and vibrational spectroscopic methods might be the key to the improvement of the current status. One hundred samples of patients with HCC and controls with cirrhosis were classified using principal component analysis together with a random forest algorithm. Differentiation of the specific spectral patterns of the studied groups was successful in more than 80%, indicating the prospect of including spectroscopy in the screening of high-risk groups, such as patients with cirrhosis.