As a consequence of the performance of a randomized controlled clinical trial on perioperative histamine release and cardiovascular and respiratory disturbances, several types of increases in plasma histamine had to be distinguished instead of only two which existed at the beginning of the study: drug-induced allergic and pseudoallergic reactions. First of all, the new classification by aetiology (clinical epidemiology) was derived from a meta-analysis (secondary analysis) of the most recent literature. According to that histamine release in the perioperative period has several, different causes and is involved in several, different disease manifestations. A clear distinction (classification), however, is necessary if histamine release as an unwanted (adverse) effect has to be recognized, value judged according to its clinical relevance and therefore also prevented by histamine antagonists. Histamine release by neuro-endocrine and neuro-inflammatory mechanisms, cytotoxic histamine release and local, cytokine induced histamine release have been distinguished from pseudoallergic histamine release, but its functions are not yet clear. It has been analysed in prospective trials which used special clinical situations as models: patients on a normal ward or before and during upper GI endoscopy without premedication, but also in specific phases of laparoscopic cholecystectomy (trocar phase and dissection phase). Their existence in the clinical reality is now very likely, but new trials must investigate the pathophysiological effects such as in metabolism, coagulation, pulmonary haemodynamics (shunt volume) and gastric acid secretion. Histamine release by pseudoallergic mechanisms, however, was identified in the very vulnerable post-induction phase of anaesthesia up to skin incision. Its incidence was much higher than ever expected and its clinical relevance was demonstrated by the severity of reactions and the intervention strategies of the anaesthetists who were blinded concerning the type of the plasma substitute given and the prophylaxis with antihistamines. Pseudoallergic histamine release was clearly unwanted (adverse). Its occurrence in the other phases of anaesthesia has to be further evaluated in the tedious procedure of data analysis of the Mainz-Marburg-trial. The overall incidence of histamine release in the trial was so incredible high (72% of all patients, some of them with up to 4 episodes of histamine release) that a distinction between pseudoallergic (unwanted) and other types of histamine release (possibly less unwanted or even beneficial) is urgently needed. In the phase of steady state (maintenance) of anaesthesia the H1-(+)H2-prophylaxis was highly effective. Further analysis must show whether this is also the case during the phases of induction of anesthesia.(ABSTRACT TRUNCATED AT 400 WORDS)