HHV-8 infection can be asymptomatic in immunocompetent individuals but poses significant risks in immunocompromised patients. As an oncovirus, it can lead to Kaposi sarcoma (KS), primary effusion lymphoma, and multicentric Castleman disease (MCD). While the association between HHV-8 and HIV is well-established, other co-infections remain underexplored due to the low incidence of HHV-8 infections. This retrospective, observational study examines twelve individuals infected with HHV-8 over seven years, focusing on patterns of co-infection and the diagnostic need for clinical management. The average age for all patients included in this study was 56 years, and a majority were male (92%). Over a majority presented with fever, night sweats, fatigue, dyspnea, and lymphadenopathy. MCD was the most common diagnosis (42%), followed by KS in the context of MCD (33%). Nearly all patients (92%) were HIV and Epstein-Barr Virus positive, with a total of 43 co-infections identified, including viral (72%), bacterial (16%), parasitic (7%), and fungal (5%) pathogens. Bacterial co-infections were more prevalent in patients diagnosed with KS than in those with MCD (p = 0.02). Given the burden of various co-infections, our findings highlight the need for comprehensive diagnostic testing to guide optimal clinical management and improve patient outcomes.