The tumour necrosis factor (TNF)/TNF-receptor (TNFR) complex plays a role in the growth of leukaemic cells. We retrospectively investigated the relationship between pre-treatment serum concentration of soluble TNFR (p55- and p75-sTNFRs) and outcome in adult acute myeloid (AML 82 cases) and lymphoid (ALL 44 cases) leukaemia. Both sTNFRs were significantly higher in AML (p55-sTNFR 4.53 ± 3.7, median 3.75; p75-sTNFR 6.51 ± 5.25 ng/ml, median 4.72) and ALL sera (3.31 ± 1.5, median 2.95; 5.30 ± 2.3 ng/ml, median 4.56, respectively) than in controls (1.89 ± 0.5, median 1.98; 2.22 ± 0.8 ng/ml, median 2.37) (P < 0.01 for both sTNFRs). Fresh leukaemic cells expressed p55- and p75-sTNFRs, which were modulated and released into the supernatant (SN) following short-term in vitro culture, suggesting that in vivo sTNFRs were also leukaemia-derived. Whereas no correlation was observed between sTNFRs and outcome in ALL, in AML higher p55-sTNFR levels (> 3.75 ng/ml) were associated with shorter disease-free survival (DFS) (P = 0.006) and overall survival (OS) (P = 0.0004). At multivariate analysis p55-sTNFR was the most significant predictor of DFS (P = 0.006) and OS (P < 0.001). Our data suggest that the prognostic significance of p55-sTNFR in AML could be related to relevant biological features of AML blasts.