Protein ubiquitination is known to result in its proteasomal degradation or to serve as a signal for tissue-specific cellular functions. Here it is reported that mice with a mutant form of the E3 ubiquitin ligase ITCH display reduced litter sizes due to a maternal effect. Mutant females had decreased numbers of implantations, corpa lutea, and extended estrous cycles. The results indicate for the first time that loss of functional ITCH disrupts female reproduction.