Rats treated with chlorphentermine 5 days a week for 4 weeks develop a phospholipidosis in their alveolar macrophages. During this time many of these cells become enlarged resulting in a population of macrophages of widely varying size. The present study was undertaken in order to examine biochemical changes which occur as the cells increase in size with the purpose of better understanding the progression of the disorder. Macrophages were lavaged from the lungs of control and chlorphenterminetreated rats. On a per cell basis, the cells from treated rats have 18 times the phospholipid content, seven times the β-N-acetylglucosaminidase activity, three times the protein content and acid phosphate activity and twice the lactate dehydrogenase activity of controls. Using centrifugal elutriation, macrophages from treated rats were separated into four fractions with mean cell volumes of 1543, 4262, 8477 and 17,052 μm3, respectively. Under the same conditions, control macrophages gave two fractions with mean cell volumes of 1289 and 1949 μm3. While phospholipid and protein content and the lysosomal enzyme activities increased linearly with increasing cell size (r > 0.99), the change in phospholipid most closely paralleled the increase in cell size. Therefore, as the cells, enlarge, they show more of an increase in phospholipid than any of the other biochemical properties studied. © 1979.