People living with HIV or AIDS (PLWHA) experienced severe medical discrimination which is seriously affecting their lives. However, few studies examined the epidemic characteristics of self-perceived medical discrimination from the discrimination objects such as PLWHA. Therefore, we aimed to investigate the epidemiological status and analyze the influential factors of the self-perceived medical discrimination on PLWHA in South China. The self-designed questionnaire was used to investigate the medical discrimination status of the 443 infected persons, who were randomly recruited from the representative AIDS designated hospitals in Guangdong Province in South China. The results showed that 49.0% of PLWHA experienced medical discrimination, and 55.3% received discriminatory treatment, 48.4% experienced refusal of treatment, 36.4% had private information leaked and 12.9% received mandatory test. However, 52.2% patients chose to endure discrimination in silence. Compared with the Asymptomatic HIV-infected patients, AIDS patients perceived more medical discrimination. The Logistic regression analysis indicated that PLWHA self-perceived medical discrimination status was influenced by 4 factors: the voluntary of first medical detection, the route of transmission, the stage of the disease and the familiarity with the HIV/AIDS-related law. Additionally, the two dimensions of the life quality scale were influenced by medical discrimination, namely, overall function and disclosure worry. Ultimately, our study provides a better understanding of the relationship between infection status, quality of life and the medical discrimination they experienced or perceived. It will help health professionals and policy makers to develop tailored behavioral and policy-oriented intervention strategies for PLWHA to tackle different types of medical discrimination in high-risk settings.