Patients with Hodgkin's disease (HD) are known to have peripheral blood lymphopenia, but the prognostic significance of this observation and its implication on immune therapy remain controversial. We determined the peripheral blood lymphocyte (PBL) counts and their subsets of 238 newly diagnosed patients with HD referred to our institution, and the quantitative changes of B, T, and natural killer cells were correlated with the patients' clinical variables. The mean white blood cell count increased steadily with advancing disease stage. In contrast, the mean absolute PBL count and its CD4, CD8, and CD3-/CD56+/CD16+ subsets, after an initial increase in stage I, steadily decreased with advanced HD stages. The mean CD20 lymphocyte count decreased steadily with advancing stage without an initial increase. Prognostic factor analysis was determined in 196 patients adequately treated with modern therapies. Neither the absolute PBL count, nor CD4, CD8, or CD20 counts correlated with shorter disease free survival. In this study, the decline in total PBL count or in its subsets in HD patients did not correlate with shorter disease free survival. Because peripheral blood lymphopenia of HD correlated with advanced clinical stage but had no independent prognostic significance, we propose that this peripheral blood lymphopenia is likely to be due to lymphocyte trafficking and homing to the diseased nodes rather than due to an absolute quantitative deficiency. Thus, strategies to improve lymphocyte functions in HD patients should continue to be explored therapeutically.