Due to the successful rollout of the Antiretroviral Therapy Program, an increasing number of perinatally HIV infected adolescents are emerging into young adulthood throughout Botswana. Young adulthood is a critical period of human development, with long-lasting implications for a person’s economic security, health and well-being. During this time, young women and men normally complete school, find employment and start working, develop relationships, form families, bear children and pursue those things that help set them on the path to healthy and productive adult life. However, the presence of a chronic illness such as HIV can interfere with the achievement of the developmental milestones of young adulthood and affect their Health Related Quality of Life (HRQOL). The purpose of this study was to identify the factors that affected the HRQOL of young adults living with perinatally acquired HIV (YALPH) and to propose policy guidelines to promote their HRQOL. A mixed-methods sequential explanatory research design was used. HRQOL assessments were made using the WHOQOL-HIV BREF instrument. Data about the clinical characteristics of the respondents was obtained from medical records. In-depth interviews were conducted with a purposefully selected subsample of respondents who completed the WHOQOL-HIV BREF instrument. All the respondents were recruited from Botswana-Baylor Children’s Clinical Centre of Excellence, in Gaborone, Botswana. Data were analyzed using SPSS Inc. software version 16.0 (statistical package for social science, SPSS Inc, Chicago, IL, USA). The study population consisted of 509 YALPH including 255 (50.1%) females and 254 (49.9%) males. The mean age of the population was 21.7 (± 2.6) years (range 18-29.8 years). The majority of the respondents were single (98.1%), living in their parental homes (90.8%), neither in school nor working (47.35%) and 14% were parents (range 1-3 children). The mean duration on ART was 12.4 years (± 4.0). Based on the BMI classifications by WHO, 38.5% of respondents were underweight (BMI < 18.5 kg/m2) and 7.3% were overweight (BMI ≥ 25.0 kg/m2). Unsuppressed viral load (>400 cell/mL) occurred in 13.4% of the sample. Most respondents had good HROQL (78.4%). The highest mean HRQOL score was recorded in the Physical domain (15.4 (± 2.9) and the lowest in the Environment domain 13.8 (± 2.7). The results fitted using the multivariable logistic regression suggest the odds for good general QOL were increased amongst individuals with a higher level of education and 6 those who were employed. The odds for good general QOL were reduced for individuals with unsuppressed viral load (> 400 cells/mm2) and those who had illnesses (self-reported). The odds for good general QOL increased by almost two folds (OR = 1.97, 95% CI = (1.11 – 3.48)) when comparing respondents with higher level of education against those with lower education. The odds for good general QOL were increased for employed respondents OR = 1.73 (95% CI = (0.92 – 3.23) when compared to the unemployed group. Whereas the odds for good general QOL declined by almost two folds (OR = 0.60, 95% CI = (0.33 – 1.08)) amongst patients with VL > 400 cell/mm2 compared to those with VL < 400 cells/mm2. Also, respondents who were ill had lower odds ratios for good general QOL compared to those who were not ill (OR = 0.42, 95% CI = (0.25 – 0.70)). The results of in-depth interviews with 45 respondents showed that the majority of YALPH were in good physical health and they had positive perspectives about the future including health, completing school, finding employment, marriage and childbearing. The main sources of social support for YALPH were close family members and health care workers (HCWs). However, worries and concerns about disclosure, fear of stigma, lack of financial independence, and limited social relationships and networks were the most identified stressors that put the YALPH at risk of compromised HRQOL. Some sub-groups of YALPH were at higher risk for poor HRQOL including: young mothers, YALPH who were aging out of institutional care, YALPH with disabilities and impairments, YALPH who were neither in school nor working and YALPH with maladaptive coping strategies. Therefore, the promotion of the HRQOL of YALPH will require policies and interventions to increase educational attainment, provide employment and livelihood opportunities, promote good ART adherence and VL suppression, and effectively prevent and manage illnesses. Special attention should be paid to sub-groups of YALPH who are at increased risk of compromised HRQOL. / Health Studies / D. Litt. et Phil. (Health Studies)