Experience of childhood trauma, especially physical, emotional, and sexual abuse, carries a risk for developing alcohol use disorder (AUD) and engaging in risky behaviors that can result in HIV infection. AUD and HIV are associated with compromised self-reported health-related quality of life (HRQoL) possibly intersecting with childhood trauma. To determine whether poor HRQoL is heightened by AUD, HIV, their comorbidity (AUD + HIV), number of trauma events, or poor resilience, 108 AUD, 45 HIV, 52 AUD + HIV, and 67 controls completed the SF-21 HRQoL, Brief Resilience Scale (BRS), Ego Resiliency Scale (ER-89), and an interview about childhood trauma. Of the 272 participants, 116 reported a trauma history before age 18. Participants had a blood draw, AUDIT questionnaire, and interview about lifetime alcohol consumption. AUD, HIV, and AUD + HIV had lower scores on HRQoL and resilience composite comprising the BRS and ER-89 than controls. Greater resilience was a significant predictor of better quality of life in all groups. HRQoL was differentially moderated in AUD and HIV: more childhood traumas predicted poorer quality of life in AUD and controls, whereas higher T-lymphocyte count contributed to better quality of life in HIV. This study is novel in revealing a detrimental impact on HRQoL from AUD, HIV, and their comorbidity, with differential negative contribution from trauma and beneficial effect of resilience to quality of life. Channeling positive effects of resilience and reducing the incidence and negative impact of childhood trauma may have beneficial effects on health-related quality of life in adulthood independent of diagnosis.