Cadmium-induced cell death is associated with endoplasmic reticulum (ER) stress. We previously found that inhibition of FBXO6 expression, which is a ubiquitin ligase involved in ER-associated protein degradation (ERAD), induces high sensitivity to cadmium in HEK293 cells. However, the precise role of FBXO6 in ER stress remains unexplored. In this study, we investigated the role of FBXO6 in cadmium-induced ER stress in HEK293 cells. Our results showed that the cadmium-induced increase in expression of the ER stress marker proteins, BiP and CHOP, was further enhanced by inhibiting FBXO6 expression. Cadmium-induced c-Jun phosphorylation was also markedly increased by inhibition of FBXO6 expression. However, this c-Jun phosphorylation was almost entirely abolished by inhibition of c-Jun N-terminal kinase 1 (JNK1) expression. The level of high cadmium sensitivity induced by inhibition of FBXO6 expression was markedly lower in the JNK1-ablated cells than in the control cells. In addition, cadmium elevated the cellular level of ERAD substrate proteins, and this elevation was further enhanced by inhibiting FBXO6 expression. These results suggest that FBXO6 might inhibit cadmium-induced ER stress by functioning as a ubiquitin ligase in the ERAD system, thereby attenuating the cell death induced by subsequent JNK1 activation.