The inhibition of the 26S proteasome evokes endoplasmic reticulum stress, which has been shown to be implicated in the antitumoral effects of proteasome inhibitors. The cellular and molecular effects of the proteasome inhibitor—bortezomib—on human colon cancer cells are as yet poorly characterized. Bortezomib selectively induces apoptosis in some cancer cells. However, the nature of its selectivity remains unknown. Previously, we demonstrated that, in contrast to normal fibroblasts, bortezomib treatment evoked strong effect on apoptosis of breast cancer cells incubated in hypoxic and normoxic conditions. The study presented here provides novel information on the cellular effects of bortezomib in DLD-1 colon cancer cells line. We observe twofold higher percentage of apoptotic cells incubated for 48 h with 25 and 50 nmol/l of bortezomib in hypoxic conditions and four-, fivefold increase in normoxic conditions in comparison to control cells, incubated without bortezomib. It is of interest that bortezomib evokes strong effect on necrosis of DLD-1 colon cancer cell line. We observe the sixfold increase in necrosis of DLD-1 cells incubated with 25 or 50 nmol/l of bortezomib for 48 h in hypoxia and fourfold increase in normoxic conditions in comparison to adequate controls. We suggest that bortezomib may be candidates for further evaluation as chemotherapeutic agents for human colon cancer.