Recessive inactivating mutations in human matrix metalloproteinase 2 (MMP2, gelatinase A) are associated with syndromes that include abnormal facial appearance, short stature, and severe bone loss. Mmp2−/− mice have only mild aspects of these abnormalities, suggesting that MMP2 function is redundant during skeletal development in the mouse. Here, we report that Mmp2−/− mice with additional mutations that render type I collagen resistant to collagenase-mediated cleavage to TCA and TCB fragments (Col1a1r/r mice) have severe developmental defects resembling those observed in MMP2-null humans. Composite Mmp2−/−;Col1a1r/r mice were born in expected Mendelian ratios but were half the size of wild-type, Mmp2−/−, and Col1a1r/r mice and failed to thrive. Furthermore, composite Mmp2−/−;Col1a1r/r animals had very abnormal craniofacial features with shorter snouts, bulging skulls, incompletely developed calvarial bones and unclosed cranial sutures. In addition, trabecular bone mass was reduced concomitant with increased numbers of bone-resorbing osteoclasts and osteopenia. In vitro, MMP2 had a unique ability among the collagenolytic MMPs to degrade mutant collagen, offering a possible explanation for the genetic interaction between Mmp2 and Col1a1r. Thus, because mutations in the type I collagen gene alter the phenotype of mice with null mutations in Mmp2, we conclude that type I collagen is an important modifier gene for Mmp2. Developmental Dynamics 236:1683–1693, 2007. © 2007 Wiley-Liss, Inc.