Background. The healthcare sector substantially contributes to global greenhouse gas emissions. While being pivotal for improving care, clinical trials involve various activities beyond routine care that contribute to their carbon footprint. We aimed to synthesize current evidence on the carbon footprint of clinical trials and the methodologies used to estimate these emissions. Methods. In this systematic review, we searched PubMed, Embase, and Cochrane databases for studies published in English until April 16, 2024. Studies focusing on the carbon footprint of clinical trials were included. Abstracts without full-text availability were excluded. Four reviewers independently extracted data, focusing on trial characteristics, carbon emission quantification methodologies, and reported emissions per trial and patient. The risk of bias was assessed using a transparency checklist for carbon footprint calculations. Findings. The review included 12 studies (6 analytical studies and 6 expert opinions). Total emissions per trial varied widely, ranging from 18 to 2,498 tons CO2eq, with emissions per patient ranging from 25 to 2,452 kg CO2eq. Methodologically, the three most recent studies included nearly all emissions domains with high levels of data completeness, whereas the other three studies considered fewer than half of the emission domains, with medium to low data completeness. Only two studies fully disclosed their conversion factors. Four expert groups agreed on the need to develop standardized estimation tools for prospective use. Experts unanimously called for the involvement of all research stakeholders in raising global awareness of the carbon footprint of clinical trials. Interpretation. The carbon footprint of clinical trials shows substantial variability, primarily due to differences in methodology and the domains of emissions assessed. Addressing these methodological inconsistencies with standardized and openly accessible tools is essential for developing strategies to reduce the environmental impact of clinical research, aligning with broader global efforts to mitigate climate change. Funding. No funding

The authors have declared no competing interest.

This study did not receive any funding

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