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Simple Summary: Cancer is becoming more common as people living with HIV (PWH) survive to older ages due to the use of effective HIV treatments. Due to this, cancer is now a leading cause of death in PWH. In this study, we used three years of data from Moffitt Cancer Center to try and understand the cancer experience in PWH, including whether cancer patients with HIV report different symptoms during cancer care compared to the general cancer population. In order to accomplish this, self-reported symptom data were collected from 12,529 patients, including 55 with HIV. We found that cancer patients with HIV were nearly 50% more likely to experience poor symptoms during their cancer care, including severe pain and depression. In addition, the presence of these symptoms was linked to the likelihood of patients dying. These findings should prompt future projects to help manage poor symptoms during cancer care for PWH. Elevated cancer-specific mortality in PWH has been demonstrated for non-AIDS-defining malignancies. However, additional clinical endpoints of interest, including patient-reported outcomes (PROs), have not been systematically examined in PWH and cancer. We evaluated differences in patient-reported symptomology between cancer patients with versus without HIV using data from 12,529 patients at the Moffitt Cancer Center, including 55 with HIV. The symptoms were assessed using the Edmonton Symptom Assessment Scale (ESAS), which asks patients to rank 12 symptoms on a scale of 1–10, with scores ≥7 considered severe. The responses across all questions were summed to create a composite score. Vital status through t July 2021 was determined through linkage to the electronic health record. PWH reported a higher composite ESAS score on average (44.4) compared to HIV-uninfected cancer patients (30.7, p-value < 0.01). In zero-inflated negative binomial regression models adjusted for cancer site, sex, and race, the composite ESAS scores and the count of severe symptoms were 1.41 times (95% CI: 1.13–1.77) and 1.45 times (95% CI: 1.09–1.93) higher, respectively, in cancer patients with HIV. Among PWH, higher ESAS scores were associated with mortality (p-value = 0.02). This is the first demonstration of uniquely poor PROs in PWH and cancer and suggests that patient symptom monitoring to improve clinical endpoints deserves further study. [ABSTRACT FROM AUTHOR]