Background <p>For nearly four decades, surgical smoke has raised concerns regarding a possible association with lung cancer in operating room staff. Various factors, including the type of surgical instrument and the nature of the dissected tissues, influence the composition of this smoke and generate biological by-products with variable toxicity.</p> Methods <p>A systematic review was conducted in PubMed and Google Scholar up to January 2024, following PRISMA guidelines. Studies were included if they evaluated the chemical composition or particle size of surgical smoke generated during procedures on human tissues, or if they investigated its mutagenic effects on human cells; animal studies, opinion papers and conference abstracts were excluded.</p> Results <p>Seventeen studies met the inclusion criteria: nine on chemical composition, five on particle size and three on mutagenicity. Surgical smoke contained several potentially carcinogenic compounds, such as benzene and formaldehyde, with particles small enough to be inhaled and reach the pulmonary alveolar region; smoke originating from adipose tissue appeared more harmful than that from lean tissue, and mutagenic and cytotoxic effects were demonstrated in breast tissue models exposed to electrocautery smoke.</p> Conclusions <p>This systematic review indirectly assesses the potential carcinogenicity of surgical smoke for operating room staff by analysing particle size, chemical composition and mutagenic potential according to the type of human tissue dissected and the instruments used. The findings suggest that specialties involving frequent dissection of adipose tissue, such as plastic surgery and oncologic breast surgery, may be particularly at risk, although no definitive causal link with lung cancer has yet been established and long-term epidemiological data are lacking.</p> Level of Evidence <p>Not gradable.</p>