Receptor-interacting protein 3 (RIP3) is an apoptosis inducing member of the RIP family. Here we report two novel splice variants of human RIP3, designated RIP3 beta and RIP3 gamma respectively. Unlike full-length RIP3, both variants possess a truncated N-terminal kinase domain and a distinct and shorter C terminus, and therefore abrogate nucleocytoplasmic shuttling and apoptosis-inducing activity. Transient expression of either variant was found to downregulate RIP3-mediated apoptosis. Importantly, real-time PCR analysis reveals that the ratio of RIP3 gamma to RIP3 is significantly increased in colon and lung cancers relative to their matched normal tissues, indicating that RIP3 gamma might be a major splice form associated with tumorigenesis.