Assessment of the influence of genetic background on the phenotype of genetically modified mice is important in evaluating mouse models of human disease. In the present study, we examined the morphological and pathophysiological aspects of the cardiopulmonary system of newborn C57BL/6J and CBA mice transgenic for the Msx1 gene. We investigated the possible influence of genetic background on the phenotype of these animals. For this, the expression of extracellular matrix components (fibronectin and collagen I) and smooth muscle ∝-actin was studied. Transgenic newborn heterozygous C57BL/6J or CBA mice showed characteristic early (neonatal/perinatal) death and shared common alterations in the cardiopulmonary system. Hematoxylin-eosin stained sections of transgenic newborn C57BL/6J mice showed myocardial infarction and lungs with congestion and hemorrhage. One CBA-derived transgenic newborn showed a few areas of cardiac mineralization while in the remaining mice of this group showed no significant cardiac alterations. All CBA-derived transgenic mice showed varying degrees of pulmonary congestion. Similar patterns of extracellular matrix and smooth muscle ∝-actin expression were observed in transgenic newborn mice derived from both strains based on light microscopy of sections stained with Gomori’s trichrome, reticulin and picrosirius plus polarization microscopy, as well as with immunohistochemical reactions for fibronectin, type I collagen and smooth muscle ∝-actin. These results indicate that the genetic background influenced the structure of the cardiopulmonary system but not the expression of extracellular matrix components or smooth muscle ∝-actin in C57BL/6J and CBA mice transgenic for Msx1.