Background: There is impetus to identify biomarkers in TGCT to help select those at high-risk of relapse following orchiectomy and target interventions to prevent over-treatment. miR-371 has been shown to reliably predict presence of active malignancy with higher accuracy than currently available biomarkers. More clinical evidence is required to ascertain its clinical utility as a marker of microscopic disease to guide treatment recommendations in stage 1 TGCT and other settings. Methods: CLIMATE ANZUP1906 (ACTRN12622000247774) is a prospective, single-arm, non-interventional cohort study recruiting adults with clinical stage 1 TGCT entering active surveillance. Eligible participants are recruited within six weeks of orchiectomy and are willing to undergo active surveillance in accordance with the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group Surveillance Recommendations (or similar), without adjuvant treatment. Participants with metastases, non-testicular primaries, or history of contralateral TGCT are ineligible. Serum, plasma, and buffy coat samples are collected at consent and every three months until 24 months (and at relapse, if applicable). miR-371 will be assessed using established protocols. Clinical data, including treatment(s), surveillance, and relapses are captured in Australia’s national TGCT registry, iTestis. Archival tissue from diagnosis ± relapse is identified for future translational research. The primary endpoint for CLIMATE is 12-month relapse-free survival of miR-371 positive/negative groups. Key secondary endpoints include miR-371 during surveillance and at relapse, concordance between serum/plasma miR-371 and archival tissue, and health economic analyses. Prior studies suggest ~20% of post-orchidectomy miR-371 samples are positive. A sample size of 200 participants will result in 20 relapses, 160 non-relapses and 20 individuals lost to follow-up, and will permit description of the primary endpoint. Patient-level data from CLIMATE will contribute to a joint analysis of parallel trials evaluating miR-371 in this setting, COG AGCT1531 and SWOG1823. The first participant was recruited to CLIMATE in February 2022. 9/12 study sites in Australia and New Zealand have been activated and 47/200 (24%) have been enrolled. Recruitment is expected to take 36 months, followed by a further 24 months follow-up. Clinical trial information: ACTRN12622000247774.