Infection of Salmonella enterica with lytic mutants of either P22 or SE1 bacteriophages triggers the expression of its DNA damage-inducible SOS response through a lexA-dependent pathway. This induction of the SOS system strictly requires the presence of the bacteriophage kil gene. Accordingly, plasmid overexpression of the kil gene also promotes the S. enterica SOS network induction. Furthermore, S. enterica Gifsy prophages are induced following the infection with SE1 and P22 lytic derivatives. The observed data reveal a hitherto unknown SOS system-mediated fail-safe mechanism of resident prophages against infection with heteroimmune lytic bacteriophages and suggest a novel role for the kil family of proteins.