Objective <p>Computed tomography-guided biopsies are needed to diagnose bone lesions, but can sometimes be challenging. We evaluated the feasibility and usefulness of photon-counting computed tomography (PCCT)-guided bone biopsies, focusing on real-time bone marrow oedema (BME) mapping to optimise diagnostic yield.</p> Materials and methods <p>This retrospective single-centre study included procedures performed from September 2024 to May 2025 using a first-generation dual-source PCCT scanner with Quantum HD mode. Ten consecutive patients underwent PCCT-guided bone biopsy with real-time BME reconstructions. The reference standard was established using histopathology or microbiological confirmation when available; clinical and ≥ 3-month radiologic follow-up for nondiagnostic or discordant results. Statistical analysis included descriptive statistics, independent unpaired <i>t</i>-tests, and correlation analysis (SPSS v22.0, RStudio).</p> Results <p>Ten patients, five women and five men, aged 60.5 ± 13.5 years (mean ± standard deviation), were included in the final analysis. The overall diagnostic yield was 70% (7/10), with a diagnostic accuracy of 87.5% (7/8) for cases with a definitive reference standard. Final diagnoses comprised tumour bone metastases (<i>n</i> = 7, 70%), bone osteomyelitis (<i>n</i> = 1, 10%), and bone marrow deposition disease (<i>n</i> = 2, 20%). Mean radiation dose (dose-length product) was 644.5 ± 112.1 mGy·cm. Monoenergetic 70-keV imaging showed significant differences between mean HU values of lytic (42.6) and sclerotic lesions (476.2) (<i>p</i> = 0.009), with a strong negative correlation between lesion morphology (sclerotic <i>versus</i> lytic) and monoenergetic 70-keV attenuation values (<i>r</i> = -0.84; <i>p</i> = 0.002).</p> Conclusion <p>PCCT-guided bone biopsy with real-time BME mapping proved feasible and showed encouraging diagnostic performance in this small exploratory cohort. Larger validation studies are needed.</p> Relevance statement <p>By combining monoenergetic images and BME mapping, PCCT-guided bone biopsy improves lesion visualisation, operator confidence, procedural efficiency, and overall safety for diagnostic tissue sampling and active disease targeting.</p> Key Points <p><UnorderedList Mark="Bullet"> <ItemContent> <p>Accurate targeting of active disease within complex bone lesions during CT-guided biopsy remains challenging sometimes.</p> </ItemContent> <ItemContent> <p>PCCT-guided biopsy with real-time BME mapping can enhance lesion targeting and procedural efficiency.</p> </ItemContent> <ItemContent> <p>PCCT-guided biopsy may improve safety, diagnostic accuracy, and operator confidence.</p> </ItemContent> </UnorderedList></p> Graphical Abstract <p></p>