Boosting antitumor T-cell function via blockade of immune checkpoint pathways such as PD-1 and CTLA-4 is one of the most prominent treatment modalities within the cancer immunotherapy armamentarium. Immune checkpoint inhibiting (ICI) biologics have been US Food and Drug Administration approved for multiple cancers, and there is a long list of clinical trials testing the efficacy of checkpoint blockade in the setting of additional malignancies. Although ICI drugs have not been clinically deployed for the treatment of infections, virus-driven cancers (eg, Merkel cell carcinoma, hepatocellular carcinoma, Hodgkin lymphoma) may also benefit from checkpoint blockade. Indeed, such studies are sorely needed because cancer remains a leading cause of death in people with HIV (PWH). Adverse events after PD-1 blockade during cancer often result from autoimmune reactions but have also been associated with infections. Research in animal models has shown that boosting pathogen-specific T-cell responses with PD-1 blockade can result in either dramatic reductions in microbial loads or host-detrimental inflammatory responses, depending on the pathogen and the timing of blockade relative to infection. PD-1 plays a particularly important role in limiting immunopathology during mycobacterial infection. We have previously shown that PD-1-deficient mice rapidly succumb to Mycobacterium tuberculosis infection. We have also shown that PD-1 blockade in Mycobacterium tuberculosis–infected nonhuman primates exacerbates tuberculosis disease. In humans, there have been multiple documented cases of pulmonary tuberculosis reactivation as well as nontuberculous mycobacterial (NTM) infections in patients with cancer after ICI administration. During viral infections in mouse models, PD-1 blockade can be either beneficial or detrimental. For example, in mice chronically infected with lymphocytic choriomeningitis virus, PD-1 blockade day 30 after infection enhances viral control, whereas PD-1 blockade before day 8 after infection leads to the death of the mouse because of extensive CD8 T-cell–driven pathology. Thus, treatment of cancers with PD-1 blockade in hosts with unresolved infections may increase the overall chance of pathogen-associated inflammatory adverse events, and it remains unpredictable under which circumstances PD-1 inhibition will be beneficial versus harmful to a host in the context of infection. We reported the case of an individual with HIV and human herpesvirus 8–associated Kaposi sarcoma who received pembrolizumab in a clinical trial assessing the safety of PD-1 blockade in this patient population. During the trial period, this individual had multiple worsening, previously controlled microbial co-infections including an enlarged NTM-infected intra-abdominal lymph node and cytomegalovirus (CMV) enteritis. Four days after the first dose of pembrolizumab, he presented with severe pain resulting from exacerbations of the intra-abdominal polymicrobial infections and was hospitalized on day 14 after infusion. In this study, we characterized soluble markers of intestinal integrity, inflammation, and peripheral antigen-specific T-cell responses to both the mycobacterial and CMV infections during this adverse event.