Measurement of the soluble form of CD8 antigen, a surface membrane component of suppressor/cytotoxic T cells, has yielded useful information relevant to prognosis in the lymphoid malignancies of childhood. We therefore determined pretreatment levels of serum CD8 antigen in 90 children with newly diagnosed Hodgkin's disease. The findings ranged widely, from 220 to 2,585 U/mL (median, 556 U/mL). In patients with advanced disease (stage III or IV), the median serum CD8 level was significantly higher than in those with less disease extension (stage I or II): 675 v 477 U/mL, P = .003. It was also higher in children with B symptoms compared with all others: 622 v 494 U/mL, P = .005. Cases with a histologic classification of mixed cellularity had a significantly higher median level of the antigen than did those classified as nodular sclerosis: 847 v 509 U/mL, P = .005. Finally, higher serum CD8 levels (greater than 430 U/mL) were significantly associated with an increased probability of treatment failure (P = .02). In a multivariate analysis, serum CD8 level retained its impact on treatment outcome after adjustment for other potentially useful prognostic factors, including disease stage, presence of B symptoms, histology, erythrocyte sedimentation rate, sex, age, and race. The prognostic strength shown by soluble CD8 in this analysis suggests that the antigen has clinical value. We postulate that increased CD8 levels in serum indicate enhanced suppressor T-cell activity, which may compromise the host's antitumor immunity, leading to unusually aggressive disease.