We aimed to investigate the determinants of optimal highly active antiretroviral therapy (HAART) adherence and time interval between successive clinic visits, and the association between these two processes. This was done by reviewing routinely collected patient information in the Centre for the AIDS Programme of Research in South Africa (CAPRISA). Records of 688 patients enrolled in the CAPRISA AIDS treatment (CAT) programme between 2004 and 2006 were analysed. Patients were considered adherent if they had taken at least 95% of their prescribed drugs. The adherence has been measured using the pill counts data. A multivariate generalised mixed random effects approach was used to jointly analyse optimal HAART adherence and time interval between successive visits. The results showed that on the overall, the association between optimal HAART adherence and time interval between successive visits was negative. The results further showed that the interaction between time and treatment site had a significant joint effect on optimal HAART adherence and time interval between successive visits. The interaction revealed that as the number of follow-up visits increased, the interval between successive visits also increased while at the same time high levels of optimal adherence were maintained in the rural treatment site. Moreover, after accounting for the time interval between successive visits, the results showed that optimal HAART adherence was significantly associated with having a cell phone, living with a partner as well as interactions that include time and gender, time and treatment site, age and gender and age and education. The findings provide evidence of a negative association between optimal HAART adherence and the time interval between successive clinic visits on the overall, which therefore indicates that longer time interval between successive clinic visits is undesirable if optimal HAART adherence is to be maintained. This notwithstanding, rural patients were able to maintain HAART adherence for longer time interval between successive clinic visits. Furthermore, the findings indicated that optimal HAART adherence was low for some sub-populations, such as the urban and male populations, thus vigorous ongoing adherence counseling is required.