A mouse model for studying anomalies of human embryonic hatching following micromanipulation is proposed. Initiation and completion of mouse blastocyst hatching was severely impaired (34/292; 12% and 28/292; 10%, respectively) with protein deprivation, resembling the situation in human in vitro fertilization. Hatching ability was restored when an artificial gap was introduced in the zona pellucida by micromanipulation at the cleaved embryo stage. This enabled 77% (285/371) and 36% (134/371) of the embryos to initiate and complete hatching in protein-free medium. No differences were found in overall cell counts between the two groups of embryos. Transfer of micromanipulated blastocysts to pseudopregnant females resulted in development of healthy fetuses. © 1992 Wiley-Liss, Inc.