We considered the prognostic factors in high-grade non-Hodgkin's lymphomas (HG-NHL) over the past two decades. In an effort to clarify the relationship between prognostic factors and therapy, we pooled the literature reports concerning 3,480 patients into four different periods according to the mean years of the clinical trials. The most important prognostic factors discovered in period A (mean year prior to 1970) were histology, symptoms and stage. In period B (1970 through 1975), in addition to the former indicators, two new factors were pointed out: bone marrow involvement and serum lactic dehydrogenase. In period C (1976 through 1980) the significance of stage was reduced, while bulk and measures of lymph nodal and extranodal involvement (LSI, ESI) were found to be better prognostic factors. In studies related to this period the prognostic role of albumin, hemoglobin and erythrocyte sedimentation rate were also emphasized. Period D (1980 through 1985) was characterized by a decrease in the importance of the Kiel and Working Formulation (WF) classifications by virtue of the better outcome, in different reports, of HG-NHL with respect to low-grade NHL. The conclusion of our analysis is that symptoms, ESI, bulk, LDH, albumin and hemoglobin should be the most important factors used today in planning the therapy and management of patients with HG-NHL. In addition, an update of the WF is necessary.