The major trials conducted on treatment simplification included large portions of patients who had previously received monotherapy or dual therapy and were likely to have relevant mutations of resistance at baseline. These studies concluded that simplification was safe (especially when this population was excluded), with some additional risk of viral failure for subjects simplified to abacavir-based regimens. On the other hand, induction-maintenance studies and other studies which involved only patients who had started HAART as the first-line showed that simplification to abacavir was as safe as continuation of the original regimen and better accepted by the patients. The largest randomized studies of simplification that allowed extrapolation of data on the population of subjects who had never received suboptimal therapy were reviewed. Four studies failed to show significant differences in efficacy between treatment arms, while two detected significant differences in favor of the continuation arms. Simplification to abacavir led to significant decreases in cholesterol and triglyceride levels and to slight improvements in quality of life. No variations in body shape were detected, although the duration was probably insufficient and most studies did not involve adequate technology (i.e. DEXA, CT). Other, smaller studies are also presented in the review, selected for their particular design or analysis, which may contribute to a better understanding of the setting in which simplification may be a feasible option. Choosing the adequate timing and the correct patient characteristics, simplification to abacavir-based regimens is safe and prevents metabolic consequences of therapy.