In HIV-infected children, long-term adherence to combination anti-retroviral therapy (cART) is difficult. In this retrospective study, we evaluated the effect of two different treatment adherence programs on treatment adherence (as indicated by cART failures) and the need for additional supportive care measures in a cohort of 31 HIV-infected children between 3 and 18 years of age. In a follow-up period of 6 years, we evaluated the treatment adherence at baseline (before introduction of any treatment adherence program in 2004) and compared this to cART failures during two treatment adherence programs (in respectively 2006 and 2009). The need for additional supportive care measures (the frequency of hospitalizations, daily observed treatment, use of child protection service, attendance of special schools, and placement in foster homes) was also evaluated at these three time points. The first treatment adherence program focused on increasing patient's obedience by imposing negative measures in case of treatment failure, whereas the second program aimed to increase treatment adherence by rewarding optimal medication intake. Prior to start of any treatment adherence intervention program, cART failures were observed in 29% of the pediatric patients. After introduction of the first treatment adherence program, cART failures decreased to 6%. During the second treatment adherence program, the cART failures remained equally low (10%), but the need for some specific additional supportive care measures (the frequency of hospitalizations and placement in foster homes) was importantly reduced. Treatment adherence programs are effective in increasing treatment adherence to cART in HIV-infected children. A novel reward treatment interventional program as an addition to social supportive care programs is a promising new positive enforcement program and can reduce the need for additional supportive care programs. Further prospective studies are needed to evaluate the long-term effect of this new treatment intervention program.