In 88 newly diagnosed lymphoma patients, tumour necrosis factor alpha (TNFα) and soluble TNF type I receptor (p55-R-TNF) were prospectively determined in plasma by immunoradiometric assay (IRMA) and ELISA methods respectively. These 88 patients included 19 with centrocyto-centroblastic lymphoma, 13 patients with other low-grade lymphoma, and 56 with high-grade lymphoma. Median TNFα plasma values were 20 pg/ml (range 5–380 pg/ml) in patients versus 7 pg/ml (range 4–9 pg/ml) in 20 healthy control subjects. Presence of TNFα level ≥20 pg/ml was significantly associated with elevated LDH level (P < 0.0001), serum β2-microglobulin level ≥ 3 mg/l (P < 0.0001), haemoglobin ≤ 12 g/dl (P = 0.0001), Ann Arbor stage III or IV disease (P< 0.005), and with bulky tumour (P = 0.01). High level of TNFα was also associated with B symptoms (P < 0.005), poor performance status (P < 0.05), and serum albumin ≤ 35 g/l (P < 0.05). Levels of p55-R-TNF were also markedly elevated in these lymphoma patients (median of 3.5 ng/ml, range 0.8–18.8 ng/ml) versus 1.45 ng/ml in control subjects (range 1.1–2.3 ng/ml). Level of p55-R-TNF ≥ 3.5 ng/ml was significantly associated with poor performance status (P < 0.0001), B symptoms (P < 0.0001), β2-microglobulin levels ≥ 3 mg/l (P < 0.0001), serum albumin ≤ 35 g/l (P = 0.0001), C-reactive protein > 6 mg/l (P = 0.0003), elevated (> 20 pg/ml) IL-6 level (P < 0.005), haemoglobin ≤ 12 g/dl (P < 0.005), and bulky tumour (P < 0.001). In the whole group of 88 patients, both high TNFα and p55-R-TNF levels strongly predicted short progression-free survival (P < 0.005 for both variables) and overall survival (P < 0.001 and P < 0.0001 respectively). In multivariate analyses the elevation of p55-R-TNF retained a higher significance over the other variables and therefore improved the predictive value of the International Prognostic Index. This study suggests that elevated TNFα and p55-R-TNF levels have a high correlation with other adverse prognostic factors in lymphoma patients and may predict a poor outcome.