A possible association between reported nocebo effects and the COMT Val158Met polymorphism has never been investigated before. The presented results are part of a study program on behavioral conditioning of immune functions. The unique advantage of the conditioning model employed here, is the ability to analyze intra-individual nocebo responses, after intake of an immunosuppressive medication during the acquisition phase of the conditioning procedure as well as after placebo intake during the evocation phase. Psychological, immunological and neuroendocrine parameters were analyzed and drug specific and general side effects were assessed before and after medication or placebo intake respectively and the three COMT genotypes were analyzed with respect to their experienced side effects. The reason for the increased sensitivity for treatment specific and general side effects in the Val158/Val158 homozygotes observed in this study is unclear. The non-synonymous single nucleotide polymorphism at COMT leads to a functional consequence. COMT harboring Val158 catabolizes dopamine three to four-times more effectively than the Met158 form. This leads to significantly lower concentrations of prefrontal dopamine in Val158/Val158 carriers compared to the other genotypes. This different availability of prefrontal dopamine seems to affect reward and information seeking behavior in general, but also predicted placebo responses in patients with irritable bowel syndrome, with more pronounced placebo responses in patients carrying the Met158 allele homozygously. A possible relationship between a smaller amount of available dopamine in the prefrontal cortex and a more pronounced nocebo response was also reported in a study with cancer patients, where patients of the Val158/Val158 genotype experienced more pain than the other two genotypes and required higher doses of morphine. Under experimental conditions however, Met158/Met158 individuals reported a higher sensitivity towards experimental pain. In order to ensure that higher rates of nocebo effects measured in Val158/Val158 homozygotes are not caused through another factor, we carefully controlled a range of possible interfering variables. These measures revealed that participants did not CHIR-99021 differ in sociodemographic variables, as well as psychological characteristics, which could have affected an increased experience of side effects, such as trait anxiety and physical characteristics. Additionally, there were no group differences in cardiovascular parameters which could have been indicators of an increased stress reaction to the experimental procedure or medication intake. Moreover, CsA levels in whole blood as well as IL-2 concentrations in culture supernatant, as an indicator of the immunosuppressive effect of CsA, were monitored with no difference between the three genotype groups which could have explained the increased CsA-specific and general side effects.