Abstract The Giant Condyloma Acuminata (GCA), the Buschke-Löwenstein tumor, is a rare and challenging pathology with a less than 0.1% prevalence. This disease is often considered a transitional phase between condyloma acuminatum and squamous cell carcinoma, potentially representing a variant of verrucous carcinoma. Despite its initially benign histological presentation, GCA can evolve into expansive papillomatous proliferations that deeply invade underlying tissues. Studies indicate that GCA may transform into invasive squamous cell carcinoma in 8.5-23.8% of cases. The strong correlation between GCA and human papillomavirus (HPV) infections, particularly subtypes 6 and 11, underscores the role of viral factors in developing this condition. The presented case involves a 57-year-old male with pre-existing medical conditions, including hypertension and diabetes mellitus, who sought emergency care due to escalating suprapubic and penile discomfort. A biopsy of the genital warts identified condyloma acuminatum with an overlying bacterial infection of Proteus mirabilis. Concurrently, pathology identified anogenital squamous cell carcinoma. Notably, the patient had no associated sexually transmitted infections and no prior immunocompromised status. Imaging studies revealed a multilobulated soft tissue mass in the pelvis with prostatic invasion and enlarged lymph nodes. Further investigations, including a transurethral resection of bladder tumor (TURBT), revealed multiple tumor deposits in the bladder, penile lesion, and suprapubic papule. Pathological examinations indicated non-invasive and invasive papillary urothelial carcinoma as well as invasive squamous cell carcinoma in different locations. The tumor was staged as pathologic IIIB T2N3M0, and a collaborative decision between Urology and Oncology teams led to the initiation of neoadjuvant chemotherapy with TIP (cisplatin, ifosfamide, and paclitaxel). The patient underwent the initial chemotherapy cycle with subsequent cycles scheduled every three weeks. Management options for GCA include radiotherapy, cryosurgery, CO2 laser surgery, systemic chemotherapy, and radical surgical excision. While radiotherapy has shown successful outcomes, concerns about anaplastic transformations and post-treatment condylomas make its utilization contentious. The absence of unequivocal guidelines for radiotherapy dosage and fractionation has led to considerations of alternative modalities, but the primary approach remains radical surgical excision. The risk of recurrence remains high due to potential tumor cell spillage during surgery. In conclusion, this case report highlights an advanced manifestation of the Buschke-Löwenstein tumor coexisting with multiple HPV infections. The complexity of GCA and the lack of consensus on optimal therapeutic strategies emphasize the need for timely diagnosis and intervention to ensure favorable prognoses. Various treatment paradigms exist in medical literature, but their efficacy varies, reflecting the ongoing challenges in managing this rare and clinically intricate condition. Citation Format: Aliya M. Khan, Sophia Navajas, Mehmet Hepgur, Samuel A. Kareff. A case of Buschke-Löwenstein tumor with superimposed infection and associated urothelial carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A018.