Although recent clinical trials have demonstrated the increasing promise of gene therapy, they have also illustrated the difficulties of assessing risks, given the inherent uncertainty of trial outcomes. An international survey was conducted to investigate gene therapy researchers' perceptions and assessments of risks in clinical trials. Data from respondents (n = 156) demonstrated researchers' perceptions of clinical context and the strength of preclinical evidence strongly influenced risk assessments and judgments of acceptable risk levels. Professional experience in clinical care, and particularly care of children, predicted favorable attitudes toward nonanimal preclinical models and trial initiation when sub-optimal treatments were available. The potential for adverse events to impact negatively on the gene therapy field and on public trust were relevant considerations when planning a trial. Decisions about clinical trials appear to be influenced not only by the clinical context and preclinical evidence, but also subjective factors reflecting the experience of researchers, value-judgments about risk and benefit, and attitudes toward preclinical models, uncertainty, adverse events, and the perceived needs of patients. It is clear that risk assessment in clinical research involves moral and scientific judgment. Identifying moral assumptions and qualitative assessments underpinning the design and conduct of research may facilitate future decision-making in clinical trials.Molecular Therapy (2013); doi:10.1038/mt.2012.230.