BACKGROUND: Despite the risks of immunosuppression, recommendations regarding screening for HIV infection prior to initiation of biologic therapies targeting common rheumatologic disorders, including inflammatory bowel disease (IBD) and inflammatory arthritides, are limited. Few cases of patients started on biologics while living with undiagnosed HIV infection have been reported. METHODS: We report three cases of patients initiated on biologics in the absence of recent or concurrent HIV screening who developed refractory disease or unanticipated complications and were later found to have undiagnosed chronic HIV infection. RESULTS: In Case 1, a 53-year-old MSM with negative HIV testing 2 years prior presented with presumed rheumatoid arthritis. He did not respond to methotrexate, so adalimumab was started. HIV testing to evaluate persistent symptoms was positive 9 months later; CD4+ T-cell count was 800 cells/μl. Antiretroviral therapy (ART) resulted in resolution of symptoms, which were attributed to HIV-associated arthropathy. In Case 2, a 55-year-old woman with injection drug use in remission and no prior HIV testing presented with hidradenitis suppurativa. She started infliximab and methotrexate therapy with good response. After she developed weight loss and lymphopenia, an HIV test was positive; CD4+ T-cell count was 334 cells/μl. Biologic hidradenitis suppurativa therapy was discontinued, with subsequent poor hidradenitis suppurativa control. In Case 3, a 32-year-old MSM with no prior HIV testing presented with presumed IBD; infliximab and steroids were started. Symptoms progressed despite IBD-directed therapy, and he was diagnosed with extensive Kaposi sarcoma with visceral and cutaneous involvement, likely exacerbated by immunosuppression. HIV testing was positive; CD4+ T-cell count was 250 cells/μl. Kaposi sarcoma initially worsened due to ART-associated immune reconstitution inflammatory syndrome. He is now improving with systemic chemotherapy and ART. HIV-associated Kaposi sarcoma is presumed to be the underlying diagnosis. CONCLUSION: All three patients had elevated risk for HIV infection, and two had final diagnoses attributed to chronic HIV infection, not warranting therapeutic immunosuppression. Screening for HIV infection prior to initiation of biologic therapy should be incorporated into clinical practice guidelines.