Background: Interleukin-6 (IL-6) is a well-known proinflammatory cytokine with tumor promoting capacity in various forms of malignancies including breast cancer (BC). Data highlighted the substantial role of HPV in the pathogenesis of BC. Compelling evidence suggests the contribution of HPV in carcinogenesis through triggering inflammatory cytokines such as IL-6. Objective: Here, we assessed the correlation between the presence of HPV infection and the status of IL-6 expression and serum level in BC. Methods: 72 tissue specimens including tumoral (Case; n=36) and their adjacent normal tissues (Control; n=36) were used. Nested-PCR and Real-Time PCR were employed to identify HPV DNA and assess the expression of IL-6, respectively. In addition, 72 sera samples from BC patients (n=36) and an age-matched healthy control group (n=36) were taken to measure the IL-6 serum level by ELISA. Results: Overall, the HPV DNA was detected in 19.4% (14/72) of samples. 33.33% (12/36) of cases and 5.5% (2/36) of the controls were found to be positive for HPV (P=0.003). The overexpression of IL-6 was observed in HPV+ samples compared to HPV- samples (P=0.05). However, the concentration of IL-6 serum level was remarkably different between patients and normal controls (P=0.0001). Intriguingly, IL-6 serum level was connected to the advanced clinical stage (III/IV), high grade (II/III), metastasis and, ER+ status of patients. Conclusions: Our finding indicated that the overexpression of the IL-6 may be connected to HPV infection in BC. Furthermore, the results reinforced the clinical significance and prognostic value of the serum IL-6 in BC patients.