A combination of immunochemical staining for HLA-DR antigens and the histochemical demonstration of enzyme activity has been used to identify specific cell populations in the normal and arthritic synovial lining layers. Such combined staining has revealed that the normal synovial lining contains a proportion of HLA-DR + ve cells, all of which show strong lysosomal enzyme activity. This population is greatly expanded in biopsies from patients with osteoarthritis and these positive cells also express strong ATPase activity. In the rheumatoid synovium five distinct cell types can be identified; all of which are HLA-DR + ve but differ in their morphology and pattern of enzyme activity. Of special interest was the discovery that a small but significant proportion of these cells have the characteristics of the interdigitating cells of the lymph node paracortex. The relationship between the emergence of these heterogeneous populations and the immunological basis of this inflammatory response is discussed.