BACKGROUND: Interleukin (IL)-12 is a cytokine that can exert regulatory effects on T and NK cells. This study was designed to identify potential developmental and reproductive hazards associated with IL-12p40 knockout in mice. METHODS: In the combined fertility and teratology study, female F0 C57/BL6 wild-type control mice and female F0 C57/BL6 IL-12p40 homozgyous knockout mice were assessed for estrous cyclicity, sperm, and mating parameters. Pregnant females were euthanized on gestation day (GD) 18 and their fetuses were assessed for external, visceral, and skeletal development. In the peri and postnatal development study, the F1 wild-type control and IL-12p40 knockout mice were assessed for developmental landmarks, sexual development, passive avoidance, motor activity, and morris water maze. RESULTS: The IL-12p40 knockout male mice exhibited decreased testis weights when compared to the wild-type control group; however, this finding was not considered adverse, as it had no apparent functional effects on mating, fertility, and pregnancy rates or sperm motility. The IL-12p40 knockout group exhibited effects on estrous cycle length, passive avoidance, morris water maze, and motor activity when compared to the wild-type control group. However, since these findings were small in magnitude, transient and/or had no apparent effects on subsequent growth and development, they were not considered adverse. CONCLUSIONS: These results demonstrate that although IL-12p40 homozygous knockout in mice exhibited effects on developmental and reproductive parameters, these effects were relatively minor and were not considered adverse. Birth Defects Res (Part B) 92:102–110, 2011. © 2011 Wiley-Liss, Inc.