Adherence may be facilitated by reducing perceptual and practical barriers to antiretroviral therapy (ART). Practical barriers include the complexity of daily dosing, while perceptual barriers include perceptions of the need for treatment and concerns about adverse effects. The study aim was to assess the effect of switching zidovudine plus lamivudine twice-daily (Combivir, CBV) to once-daily tenofovir DF plus emtricitabine (Truvada, TVD), each plus efavirenz (EFZ), on adherence, beliefs about ART and quality of life (QoL). Subjects stable on CBV + EFV were randomised 1:1 to continue this regimen or switch to TVD + EFV. Adherence was measured using the Medication Adherence Self-Report Inventory at 4, 12, 24 and 48 weeks. Beliefs about ART (perceptions of necessity and concerns about adverse effects), treatment intrusiveness and QoL were measured by questionnaire at baseline 4, 12, 24 and 48 weeks. Viral load was assessed at each visit. Two hundred and thirty-four subjects initiated treatment. At week 48, the proportion of subjects reporting high adherence (≥95% taken as prescribed) was significantly greater in the TVD arm (p=0.049). Low adherence (reporting taking <95% as prescribed, discontinuing the study or having missing data) was associated with doubts about necessity (p=0.020), stronger concerns about adverse effects (p=0.010), greater treatment intrusiveness (p=0.010) and poorer mental health related QoL (p=0.008). At week 48, both concerns about ART (p=0.038) and treatment intrusiveness (p=0.004) were lower among those who switched to TVD. Furthermore, there was a decline in both concerns about ART (p=0.007) and treatment intrusiveness (p=0.057) over the 48 weeks among those who switched to TVD. There were no significant differences in necessity beliefs, QoL or viral load between randomised groups. Switching from CBV to TVD may improve patient reported outcomes including slightly better adherence, a greater reduction in concerns about adverse effects and less treatment intrusiveness.