Background: The most recent studies indicate that Human papillomavirus (HPV) vaccination could have the potential to treat squamous cell cancer, basal cell carcinoma, and genital and cutaneous warts. We aimed to assess the efficacy as well as the safety of the quadrivalent HPV vaccine (GARDASIL) versus 5-fluorouracil in the treatment of basal cell carcinoma (BCC). Methods: This clinical trial has been performed on 20 patients with confirmed diagnosis of BCC, they were subdivided into two equal groups (n=10 for each), Group I: were treated with intralesional injections of Gardasil (0.2 - 0.5 ml) based on the size of the lesions. The injections were administered every two weeks for a total of five sessions, Group II: were treated with intralesional injections of 0.3 ml 5-flourouracil (50 mg/ml) using an insulin syringe every two weeks for a total of five sessions. Assessment of therapeutic response, as well as adverse events were done at the end of treatment. Results: The treatment response observed in the studied cohorts revealed a statistically significant improvement, with a higher proportion of marked and complete responses in the 5-Fluorouracil group compared to the Gardasil HPV vaccine group (p = 0.004). This highlights the effectiveness of 5 Fluorouracil in achieving higher response rates among participants. Pain during injection was common in both groups and it was (mild and tolerable). Mild headache was the most common constitutional manifestation associated with Gardasil vaccine. Conclusion: Intralesional 5-fluorouracil seems to be good therapeutic option for BCC, particularly for patients seeking less invasive treatments. While GARDASIL showed limited effectiveness in treating BCC.