Non-compliance with Antiretroviral Therapy is a major public health concern and further challenged by interaction of various social and clinical obstacles. So; near perfect pill taking is desirable in order to maximise its benefits. To systematically search, appraise and synthesise the best available evidence on determinants of non-compliance with Antiretroviral Therapy among adults living with HIV/AIDS and provide direction to future how to increase compliance with Antiretroviral Therapy. The systematic review considered studies with 18 years and above year old adults living with HIV/AIDS.Determinants of non-compliance with Antiretroviral Therapy among adults living with HIV/AIDS.Quantitative study designs were considered for inclusion.Socio-economic, Health service, Psychosocial and behavioural and Clinical related outcomes. English language articles published between January1997 and December 2011 were sought across major databases. Methodological quality was assessed using Joanna Briggs Institute Meta Analysis of Statistical Assessment and Review Instrument critical appraisal tools. Data were extracted from papers included in the review by using a standardized data extraction tool. Meta- analysis was conducted using fixed and random effects model with mantel Haenszel method using Revman5 software. Heterogeneity between the studies was assessed using χ test at a p-value of <0.05. Summary statistics were expressed as adjusted odds ratio or adjusted risk ratio with 95% confidence intervals at a p-value of <0.05. Nine studies (seven cross-sectional, one cohort study and one case-control study) were included in the review. Results from meta analysis showed that white race adults living with HIV/AIDS were 1.38 times more likely to non-comply with Antiretroviral Therapy when compared with black adults living with HIV/ AIDS (Adjusted Relative Risk=1.38; 95%CI=1.21, 1.58, p value<0.00001). Non-depressed adults living with HIV/AIDS were 1.77 times more likely to non-comply with Antiretroviral Therapy when compared with depressed adults living with HIV/AIDS (Adjusted Odds ratio =1.77; 95%CI=1.17, 2.69, p value=0.007). Substance non-user adults living with HIV/ AIDS were 2.04 times more likely to non-comply with Antiretroviral Therapy when compared with substance user adults living with HIV/ AIDS (Adjusted Relative Risk =2.04; 95%CI=1.51, 2.74, p value=<0.00001). Adults living with HIV/ AIDS with baseline CD4 count ≥200cells/ml were 1.8 times more likely to non-comply with Antiretroviral Therapy when compared with adults livings with HIV/ AIDS with baseline CD4 count ≥200cells/ml (Adjusted Odds ratio=1.84; 95%CI=1.08, 3.15, p value=0.03). We found the base line CD4 count ≥200cells/ml, not being depressed; not using substances and being white in race were associated with non-compliance with Antiretroviral Therapy.Behavioural change via counselling should be encouraged as a way to increase compliance. Reminders to take mediations regularly, on time, offering encouragement to keep going, helping to keep clinic appointments and providing emotional support for adults living with HIV/AIDS is important.Further research utilizing more robust experimental methods would help to further explore the findings of this review.