Background Sternal lesions are occasionally seen in clinical practice and their diagnosis can be important, especially for oncologic patients. However, percutaneous computed tomography (CT)-guided biopsy of sternal lesions is rarely performed. Purpose To assess the diagnostic yield of percutaneous CT-guided sternal biopsies and to analyze the factors that affect diagnostic yield. Material and Methods A retrospective review of 34 patients who underwent CT-guided sternal biopsy was carried out at a single institution. Pre-biopsy CT density, location, penetration length of biopsy needle, number of biopsy attempts, angle of needle approach, final diagnosis, and operator experience level were recorded. A biopsy was considered as diagnostic if it provided a confident pathologic result. All variables were compared using Chi-square tests. Results Twenty-two of the 34 (64.7%) biopsy procedures yielded a diagnostic sample and 12 (35.3%) were non-diagnostic. Eight participants in the non-diagnostic group were clinically diagnosed with inflammatory arthritis of the manubriosternal or costosternal joints. Longer penetration distance of the tumor by the biopsy needle showed higher diagnostic yield ( P = 0.031). Osteoblastic lesions ( P < 0.001), lesions in the manubriosternal joint ( P = 0.018) and approaches using more obtuse angles ( P = 0.009) were associated with significantly lower diagnostic yields. Malignancy in the final diagnosis led to a higher diagnostic yield than benign lesions ( P < 0.001). Conclusion CT-guided percutaneous sternal biopsy has a relatively lower diagnostic yield. However, acute angle of needle approach may help increase biopsy success rate. Osteoblastic lesions and lesions in the manubriosternal joint tend to have lower diagnostic yield.