Spleen, lymph node, bone marrow, and thymus cells from Friend leukemia virus (FLV)-infected mice were examined by scanning electron microscopy. Whereas splenocytes from normal, noninfected animals showed the expected morphological classes of lymphocytes, including cells with numerous villous projections and smoother cell types, spleen cells from mice infected with FLV showed a rapid alteration of surface morphology. Shortly after infection, a decrease in the number and percentage of villous cells occurred, with a concomitant increase in the number of cells that were larger and smoother. Within 10 to 20 days after infection, the majority of splenocytes were smooth, large cells showing many distinct morphological charges, including surface "holes" and a "spongy" appearance. By days 25 to 35 after infection, most splenocytes were abnormal in appearance. Similar changes occurred in the lymph nodes after FLV infection, but the rate of change was much lower. Abnormal and larger smooth-surfaced cells did not become prominent until after week 2 or 3 infection. Thymus and bone marrow cells showed little if any change in surface morphology until late in the infectious process. However, even at that time only a few of the cells were abnormal in appearance. The changes in cell population in the spleen but not the lymph nodes paralleled the rapid decrease in the percentage of cells which stained positive for surface immunoglobulin and theta antigen. Futhermore, FLV antigen rapidly appeared on spleen cells after infection; fewer lymph node cells were positive, and only low numbers of marrow and thymus cells stained positive for FLV antigen. The marked immunosuppression induced by FLV infection paralleled and in some instances preceded the marked morphological changes.