Lymphocyte homing receptors (HRs) mediate lymphocyte binding to high endothelial venules, and control their circulation between the blood and the lymphoid organs. The role of HRs and nuclear DNA content in the spread and prognosis of non-Hodgkin's lymphoma was studied from paraffin-embedded tumor sections of 104 patients followed-up for the minimum of 5 years after the diagnosis. HR expression was analyzed by staining with a monoclonal antibody, Hermes-3, and DNA content by flow cytometry. Ten (10%) lymphomas were HR negative (HR-), 14 (13%) weakly (HR+/-), and 80 (77%) strongly positive (HR+). HR- lymphomas disseminated less often than HR+/- or HR+ lymphomas (P = .03), and their prognosis was more favorable (P = .03), although they often had a large S phase fraction (SPF), indicating a rapid proliferation rate. A large SPF (greater than 12%) was strongly associated with an unfavorable histologic type in Working Formulation (P = .0001) and poor survival (P = .006), whereas DNA aneuploidy was not. The 5-year survival rate corrected for intercurrent deaths was 61% in lymphomas with SPF less than 12% or with HR-, but only 15% if SPF was greater than 12% and HR+ (P less than .0001). In multivariate analysis stage (P less than .001), SPF (P = .002) and HR (P = .003) were the only independent prognostic factors.