BACKGROUND: Bladder cancer is the most common malignancy of the urinary tract, and is characterized by a high risk of recurrence and mortality. Therefore, the research is still ongoing to determine new molecular markers that would be a part of bladder cancer diagnosing approach. Based on the above, this study determined the level of HMGA2 protein in bladder cancer tissues for the purpose of investigating the possibility of proposing it as a promising diagnostic marker, as HMGA2 is an architectural transcription factor that regulates cell proliferation, cell differentiation, and apoptosis. METHODS: Forty primary transitional cell bladder samples and 20 adjacent normal tissue samples were collected from patients at Al-Assad University Hospital in Damascus between March 2023 and January 2024. Immunohistochemical staining was used to assess HMGA2 protein levels. The relationship between HMGA2 tissue levels and clinical variables was analyzed using the Chi-Square Independence Test. RESULTS: This study showed that HMGA2 protein was overexpressed in 70% of bladder cancer tissues, with no expression in normal tissues. Also, a High HMGA2 levels were noticed to be significantly associated with advanced tumor stage, higher tumor grade, and muscle invasion (p < 0.05). No significant association was found between HMGA2 levels and gender or smoking habits. CONCLUSION: HMGA2 protein is overexpressed in bladder cancer tissues and correlates with tumor progression and aggressiveness. HMGA2 can be considered a promising marker for bladder cancer. Further studies with larger patient cohorts are needed to confirm these findings and establish HMGA2 as a reliable diagnostic tool.