Human cytomegalovirus-infected fibroblasts are resistant to the induction of apoptosis by superinfection with a mutant adenovirus unable to produce the viral E1B 19-kDa protein that normally causes an E1A protein-mediated apoptotic response. Two cytomegalovirus gene products that block apoptosis were identified. The IE1 and IE2 proteins each inhibit the induction of apoptosis by tumor necrosis factor alpha or by the E1B 19-kDa-protein-deficient adenovirus but not by irradiation with UV light. Our results suggest a new physiological role for the IE1 and IE2 proteins in the human cytomegalovirus replication cycle.