Abstract Intrathoracic cancers, including lung cancer, mesothelioma, and thymoma, present diagnostic challenges in primary care. Biomarkers could resolve some challenges. We synthesized evidence on biomarker performance for intrathoracic cancer detection in low-prevalence settings. A search in Embase and MEDLINE included studies that recruited participants with suspected intrathoracic cancer and reported on at least one diagnostic measure for a validated, noninvasive biomarker. Studies were excluded if participants were recruited based on a preestablished diagnosis. A total of 52 studies were included, reporting on 108 individual biomarkers and panels. Carcinoembryonic antigen, CYFRA 21-1, and VEGF were evaluated for lung cancer and mesothelioma. For lung cancer, carcinoembryonic antigen and CYFRA 21-1 were the most studied, with AUCs of 0.48 to –0.90 and 0.48 to –0.83, respectively. Pro–gastrin-releasing peptide (Pro-GRP) and neuron-specific enolase (NSE) had the highest negative predictive values (NPV) (98.2% and 96.9%, respectively), whereas Early Cancer Detection Test - Lung (Early CDT) and miRNA signature classifier panels showed NPVs of 99.3% and 99.0%, respectively, in smokers. For mesothelioma, fibrillin-3 and mesothelin plus osteopontin had AUCs of 0.93 and 0.91, respectively. Thymoma panels (binding AcHR + StrAb and binding AcHR + modulating AcHR + StrAb) had 100% NPVs in patients with myasthenia gravis. The review highlights the performance of some biomarkers. However, few were evaluated in low-prevalence settings. Further evaluation is necessary before implementing these biomarkers for intrathoracic cancers in primary care.