The precise biological mechanisms that caused the TGN1412 clinical trial tragedy (also known as ‘The Elephant Man Clinical Trial’) in March 2006 remain a mystery to this day. It is assumed widely that the drug used in this trial (TGN1412) bound to CD28 on T lymphocytes and following activation of these cells, a massive ‘cytokine storm’ ensued, leading ultimately to multi-organ failure in all recipients. The rapidity of this in vivo response (within 2 h), however, does not fit well with a classical T lymphocyte response, suggesting that other ‘faster-acting’ cell types may have been involved. In this study we have activated purified human peripheral blood leucocyte populations using various clones of mouse monoclonal anti-CD28 presented to cells in the form of a multimeric array. Cytokines were measured in cell-free supernatants at 2 h, and specific mRNA for tumour necrosis factor (TNF)-α, thought to be the initiator of the cytokine storm, was also measured in cell lysates by reverse transcription–polymerase chain reaction (RT–PCR). Monocytes were the only cell type found to show significant (P < 0·05) up-regulation of TNF-α at 2 h. Eleven other monocyte cytokines were also up-regulated by anti-CD28 within this time-frame. It therefore seems likely that monocytes and not T cells, as widely believed, were probably responsible, at least in part, for initiating the cytokine storm. Furthermore, we propose that a multimeric antibody array may have formed in vivo on the vascular endothelium via an interaction between TGN1412 and CD64 (FcγRI), and we provide some evidence in support of this hypothesis.