Some adverse non-drug-related symptoms are highly prevalent among normal populations. Therefore, such symptoms are likely to be reported as adverse events during the course of phase I studies. This study evaluated the adverse non-drug-related symptoms in a group of 192 healthy volunteers for phase I studies and a group of 117 healthy subjects who matched the volunteers group in terms of sociodemographic characteristics.Both groups completed a questionnaire on the occurrence of complaints during the previous 4 weeks. In volunteers to phase I studies, the questionnaire was applied immediately before their admission to participation.The mostly commonly reported complaints (volunteers vs. control) were headache (44.8% vs. 55.6%) and back pain (41.4% vs. 52.1%). Compared with the control, subjects who volunteered for phase I studies presented significantly lower prevalence on the following symptoms: stomach pain (p = 0.002); back pain (p = 0.008); limb or joint pain (p = 0.003); headaches (p = 0.044); fainting spells (p = 0.005); palpitations (p = 0.018); shortness of breath (p = 0.005); constipation, loose stools, or diarrhea (p = 0.033); nausea, gas, or indigestion (p = 0.019); feeling nervous or anxious (p = 0.001); feeling restless (p = 0.011); getting tired very easily (p < 0.001); muscle tension, aches, or soreness (p = 0.007); and concentration difficulties (p = 0.003).Participants in phase I studies are a self-selected sample with a lower tendency to report non-drug-related adverse events than their peers from the normal population. The impact of this self-selection bias on the assessment of tolerability during phase I studies results deserves further evaluation.