Cysteine cathepsins are important regulators and signaling molecules of an unimaginable number of biological processes, while they concurrently play an essential role in cancer progression, invasion and metastasis. The purposes of our study were to: a) compare the expression levels of cathepsins B, H and L in the supernatants of colon cancer tissues from 74 patients versus the corresponding enzymic expressions of supernatants in the adjacent normal colorectal tissues; and b) correlate our results to the grade of the malignancy by using an enzyme-linked immunosorbent assay (ELISA). The findings indicated that cathepsins B, H and L of all malignant tissues exhibited significantly higher expression levels than their corresponding controls. Furthermore, cathepsin B expression levels doubled in all tumor samples and this increase remained quite steady with tumor stage advancement, in contrast to cathepsin H expression which rose significantly as malignancy progressed. Specifically, cathepsin H concentration was higher than the corresponding control: 155% in B1 stage and 204.44% in D stage. Among the three investigated proteases, cathepsin L has shown the highest increase, which in D stage stood 261.03% higher than the corresponding control. The results at hand suggested that cysteine protease H and L expression levels could be of critical value in the diagnosis and progression of colon cancer.