Background: Receptor tyrosine-protein kinase ERBB2, also known as human epidermal growth factor receptor-2 (HER2), is heterogeneously expressed in a variety of human cancers, including bladder cancer. Based on previous studies that show its association with bladder cancer progression, HER2 has been included in novel multiplatform biomarkers for prediction of bladder cancer prognosis. However, the clinical significance of HER2 status remains underinvestigated and poorly linked to the patients’ clinicopathological features. Here, we aim to scrutinize the levels of the extracellular domain of HER2 in the sera of bladder cancer patients and correlate these levels with clinicopathological features of the tumor.Methods: In the present analytical cross-sectional study, we enrolled 60 pathologically confirmed bladder cancer patients along with 20 age-sex matched healthy controls, and compared their serum HER2 levels as measured by enzyme-linked immunosorbent assay.Results:We observed no statistically significant difference when comparing the levels of HER2 in the sera of cases and controls (P>0.05). Interestingly, serum HER2 levels of controls were higher than bladder cancer patients who had lymph node metastasis (P=0.036). Serum levels of HER2 were also higher in controls than bladder cancer patients with perineural invasion (P=0.028). We observed significantly higher HER2 serum levels in transitional cell carcinoma patients in comparison to non-transitional cell carcinoma patients (P=0.016).Conclusion: Our observations are suggestive of the absence of any association between bladder cancer prognostic factors and serum HER2 levels. To draw any definitive conclusion, further studies with larger sample sizes that examine the presence of neutralizing auto-antibodies against serum HER2, immunohistochemistry examination of HER2 in bladder tumor and lymph node samples, and urinary HER2 levels, along with measurement of its serum levels would be helpful.