Phase 1 clinical trial participants could potentially be exposed to significant health risks. Findings from a standard battery of genetic toxicology tests typically are the only data available to inform about cancer hazards at the initiation of clinical trials. Although uncommon, a question occasionally arises that is not clearly defined in current guidance: how many doses of an Ames-positive (potentially DNA-reactive) drug can be administered safely to healthy adult subjects during Phase 1 clinical trials? A literature survey was undertaken to identify information on carcinogenic risks from short-term exposures to Ames-positive agents, which might inform about administering an Ames-positive drug as a single dose or over a period of up to 14 days in healthy adult subjects. Limited information was identified on risk predictions for short-term exposures from modeling applications and from human studies, with more extensive data available using animal models. Relevant information on cancer outcomes following short-term exposures to Ames-positive agents suggest there is an increased cancer risk for administering even a single dose of an Ames-positive drug to healthy adult subjects. These findings indicate that Phase 1 studies with Ames-positive drug candidates should be exceedingly rare, and that additional mutagenicity testing should be performed before drug administration.