The purpose of the study was to evaluate the reliability and validity of the two generic instruments, the WHOQOL and the SF-36, for assessing health-related quality of life in 224 patients with HIV infection. The internal consistency ranged from 0.75 to 0.86 across the WHOQOL-BREF domains and from 0.72 to 0.93 across the SF-36 scales. The scores of all WHOQOL-BREF domains and SF-36 scales correlated positively with the measure of happiness, Sat-HRQOL and self-perceived health status, and correlated negatively with the number and intensity of symptoms. Patients with higher CD4 cell counts scored significantly higher on G4 (general health), three WHOQOL-BREF domains, seven SF-36 scales, and PCS (physical component summary). Patients with fewer symptoms and with less intensity of symptoms had significantly higher scores on all four domains of WHOQOL-BREF, eight scales, PCS, and MCS (mental component summary) of the SF-36 scale. The correlations between the physical, psychological, and social domains of the WHOQOL-BREF and PF (physical functioning), MH (mental health), and SF (social functioning) of the SF-36 were 0.51, 0.75, and 0.54, respectively. There is also good correlation between PCS of the SF-36 and the physical domain of the WHOQOL-BREF (r = 0.48), and between MCS and all four domains of the WHOQOL-BREF (r range = 0.60-0.75). The WHOQOL-BREF domains showed fewer floor or ceiling effect than the SF-36 scales. We concluded that both the WHOQOL-BREF and the SF-36 are reliable and valid health related quality-of-life instruments in patients with HIV infection.