Three mutants of the C57 BL/6J strain, i.e., the tight-skin (Tsk), pallid (pa), and beige (bg) mice have been reported to develop spontaneous emphysema. However, the pathogenic mechanisms of this lesion may be different in the three mutants. Differences and similarities of these models were investigated by means of scanning electron microscopy. A light microscopic investigation provided the background for the SEM study. C57 BL/6J (control), pa, Tsk, and bg mice were killed when they were 1, 12, and 24 months old. At light microscopic investigation the lungs of the controls appeared normal at all ages. Those of the pa mice had normal appearance at 1 month, showed a few areas of air space enlargement with destruction of alveolar septa at 12 months, and had a generalized enlargement of the air spaces associated with distortion of alveolar septa at 24 months. The Tsk mice had a generalized panlobular emphysema at all ages. The lungs of the bg mice showed at all ages a generalized enlargement of the air spaces not accompanied by changes of the alveolar septa. At scanning electron microscopy the lung parenchyma of control mice was essentially normal at all ages. Both alveolar ducts and alveoli increased in size (the latter also in depth) with age. The number of interalveolar pores (Np) increased by 54% between 1 and 12 months of age and by 49% between 12 and 24 months. The parenchyma of pa mice did not differ significantly from that of the controls at 1 month. At 12 months the alveoli appeared to be larger. At 24 months in some fields alveolar ducts were enlarged, the alveoli were also enlarged and very shallow. Np was not different from controls at 1 month but greater at 12 (+ 49%) and 24 (+ 26%) months. The parenchyma of Tsk mice of all ages appeared distorted with enlargement of alveolar ducts and sacs and with alveoli with a large number of pores. These changes increased with age. Np was larger than the controls at all ages (+ 59% at 1 month, + 119% at 12 months, and + 80% at 24 months). The parenchyma of the bg mice of all ages appeared disorganized with large alveoli of different shapes. There was a deterioration with age. No difference in Np was seen at any age between bg and control mice. Parenchymal changes characterized by distortion and enlargement of alveolar ducts and sacs were observed, even if with different onset and extent, in all mutants. However, an increase in Np, which is considered to represent the early development of emphysema, was found only in Tsk and pa mice. In Tsk mice, high Np values were observed at all ages, whereas in pa mice Np was increased only late in life when the pulmonary lesion develops. These differences indicate different pathogenetic mechanisms for these three mutants.