Tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) is a potent inducer of apoptosis in sensitive cells and may be suitable for novel anti‐cancer therapies aimed at inducing apoptosis via the activation of TRAIL receptors on malignant cells. Here we have characterized the TRAIL sensitivity of a panel of Burkitt's lymphoma (BL) cell lines. Overall, 5/12 BL cell lines and 1/2 lymphoblastoid cell lines were sensitive to TRAIL‐induced apoptosis, although only one BL cell line approached the sensitivity of Jurkat cells, a widely used model for TRAIL‐induced apoptosis. Whereas, 4/5 of the Epstein–Barr virus (EBV)‐negative cell lines were TRAIL sensitive, only 1/7 EBV‐positive BL cell lines were TRAIL sensitive. However, isogenic BL cell lines with different EBV status were not differently sensitive to TRAIL, indicating that EBV is not a major determinant of TRAIL sensitivity. All cell lines expressed the death receptor (DR)5 TRAIL receptor, whereas expression of DR4 was more variable. Differences in the expression of downstream signalling molecules [Fas‐associated death domain protein (FADD), caspase 8] and inhibitors [decoy receptor 1 (DcR1), cellular FLICE‐like inhibitory protein (c‐FLIP)] did not correlate with TRAIL sensitivity. Therefore, a subset of BL cell lines are sensitive to TRAIL‐induced apoptosis, however, the molecular mechanism that determines responsiveness remains to be identified.