Ensuring the wellbeing of people living with HIV (PLWH) has become a significant public health concern in the era of highly active antiretroviral therapy. This study was to assess the quality of life (QoL) among PLWH in South Carolina (SC) and to examine the relationship between self-reported viral load (VL) suppression and their perceived QoL. In 2018, a cross-sectional survey was conducted among 402 PLWH from a large immunology clinic in SC. The WHOQoL brief version (WHOQoL-HIV-BREF) instrument with six domains (physical health, psychological health, social relations, independence, environmental health, and spirituality) and two specific questions (overall rate of QoL and satisfaction with health) were used. On a five-point scale, the participants rated their overall rating of QoL as good (mean = 4.07). The participants reported their psychological health as the highest (mean = 3.88) followed by environmental health (mean = 3.82), social relations (mean = 3.69), and independence (mean = 3.47). 71% reported an undetected VL. In multivariable analyses, self-awareness of undetected VL was significantly associated with satisfaction with health, psychological health, social relations, environmental health, but negatively associated with spirituality. These findings suggest that self-awareness of undetected VL had a significant impact on their perceived QoL beyond sociodemographic factors among PLWH who were linked to care in SC.