Although bleomycin-induced cellular injury in the lung parenchyma is followed by the development of patchy fibrosis, the authors hypothesized that remodeling of the interalveolar septum (IAS) following bleomycin is a diffuse process not limited to the formation of discrete fibrotic areas. To determine the spectrum of changes in the IAS induced by bleomycin treatment, lungs were harvested from mice at 1, 2, 3, and 4 weeks following intratracheal administration of 0.04, 0.06, or 0.08 units of bleomycin. Light microscopy with quantitative morphometric techniques and electron microscopy were used to evaluate the IAS alterations. At 4 weeks after treatment, there was evidence of diffuse IAS remodeling. By morphological analysis, two types of structural remodeling of the IAS were observed. One type showed thickening with extracellular matrix deposition and hyperplasia of lining epithelial cells. The other type showed localized thinning of the interstitium with capillary loss and reduction in number and in size of epithelial cells. The authors have defined these variants as septal thickening and septal atrophy, respectively. The findings indicate that studies investigating the pathogenesis of lung fibrosis should focus on septal remodeling as well as analysis of fibrotic foci and measurement of collagen content.