Really interesting new gene (RING) finger proteins represent a large protein family in the human genome, and play crucial roles in physiological activities and cancer development. The biological functions of some RING finger proteins remain unknown. Here, we described the biological activity of a novel, human Golgi-localized RING finger protein 121 (RNF121), the function of which is, thus far, unknown. Unlike the endoplasmic reticulum-localized RNF121 in Caenorhabditis elegans, human RNF121 is predominantly localized to the Golgi apparatus. RNF121 knockdown inhibited cell growth and induced apoptosis, which was accompanied by caspase-3 activation and the cleavage of poly (adenosine diphosphate-ribose) polymerase. Z-VAD-FMK, a pan-caspase inhibitor, inhibited the RNF121 knockdowninduced apoptosis. Over-expression of wild-type RNF121, but not the RING domain mutants of RNF121, decreased RNF121 knockdown-induced apoptosis, indicating that the RING domain is required for RNF121-regulated apoptosis. Moreover, RNF121 knockdown enhanced etoposide-induced apoptosis. This is the first study to demonstrate that RNF121 is a novel regulator of apoptosis and provides a new potential target for cancer therapy.