The occurrence of chemoresistance is a serious problem in the treatment of cancer, urging the need for second and third-line treatment options that rely on different cell death pathways to overcome previously acquired resistance mechanisms. The inhibition of proteasomal activity by specific proteasome inhibitors or cross-reactivity of certain protease inhibitors with proteasomal enzymes recently became of interest because of the anti-tumoral properties of these agents. We tested the proteasome inhibitor bortezomib and the HIV protease inhibitor nelfinavir on human cervical cancer cells. Both drugs induced cell cycle arrest in cervical cancer cells, as reflected by marked changes in the expression of cell cycle-regulatory cyclins and ensuing mitochondrial-independent apoptosis. Upregulation of the molecular chaperone BiP and the cell stress marker ATF3 indicated induction of the unfolded protein response (UPR) as the main cause of apoptosis induced by these drugs in cervical cancer cells. Unlike in leukemia cells, bortezomib mainly inhibited the caspase-like activity of the proteasome in cervical cancer cells. Nelfinavir exhibited no effects on proteasomal activity in cervical cancer cells and leukemia cells. Although both bortezomib and nelfinavir acted on cisplatin-resistant cervical cancer cells (SiHa), neither of the drugs induced a sensitization to cisplatin treatment. Instead, both drugs could effectively be combined with each other, and enhanced the efficacy of an apoptosis-inducing TRAIL receptor antibody. These results suggest that both bortezomib and nelfinavir are effective agents against chemoresistant cervical cancer cells and might be of interest for clinical studies on cervical cancer patients with recurrent or metastatic cancer.