Monoclonal antibodies (mAbs) have been a spectacular clinical and commercial success in the treatment of cancer and autoimmune diseases. Many of these mAbs (for example, OKT3, Campath-1H, rituximab and infliximab) are against surface or secreted products of lymphocytes. However, mAbs can have a variety of adverse effects including fever, chills and nausea. This is probably a result of cytokine release, which is most seriously manifested as a ‘cytokine storm' as highlighted by the TGN1412 (anti-CD28) trial. Prediction of adverse effects of mAbs would be clinically advantageous and numerous in vitro assays attempting to predict adverse effects have been reported. Here, we report an in vivo humanized mouse model to detect adverse effects in response to OKT3, Campath-1H or the polyclonal Ab preparation anti-thymocyte globulin. We found that the administration of each of these Abs to humanized mice led to acute clinical symptoms such as piloerection, hypomotility and hypothermia, particularly when delivered via the intravenous route. A cytokine storm occurred in the humanized mice receiving OKT3. This model system is a potentially useful tool to predict adverse effects and select initial doses for first-in-human trials. We would advocate this in vivo model, in addition to current in vitro preclinical testing, as a more representative and robust means of assessing potential adverse effects of mAb before their human use.