General self-efficacy (GSE), the expectation that one is able to perform a behavior successfully, may differentiate those who are able to successfully utilize self-care symptom management strategies (SCSMS). This subanalysis (n=569) of an international 12 site longitudinal randomized controlled trial (RCT) (n=775), investigated GSE as an important factor determining symptom burden, SCSMS, engagement with the provider, and medication adherence over time, and identified differences in those with high and low GSE ratings concerning these variables. Parametric and nonparametric repeated-measures tests were employed to assess GSE and the perceived effectiveness of SCSMS for anxiety, depression, diarrhea, fatigue, nausea, and neuropathy. Symptom burden, engagement with the provider, and antiretroviral adherence were analyzed with regard to GSE. Our data indicated that there were differences in the perceived symptom burden over time of HIV infected individuals by GSE. Those individuals with higher GSE had fewer symptoms and these symptoms were perceived to be less intense than those experienced by the low GSE group. There were few meaningful differences in the SCSMS used by those with high versus low GSE other than the use of illicit substances in the low GSE group. The low GSE group was also significantly (p= < 0.001) less engaged with their healthcare providers. Given the difference in substance use by perceived GSE, and the importance of engagement with the healthcare provider, more attention to the resolution of the concerns of those with low GSE by healthcare providers is warranted.