Background: Non-adherence to combination antiretroviral therapy leads to drug resistance, treatment failure and increased morbidity and mortality among HIV positive adolescents. The aim of this study was to assess factors influencing adherence to combination antiretroviral therapy among HIV positive adolescents at Adult Infectious Disease Center in Lusaka, Zambia. Methodology: A descriptive quantitative cross sectional study was conducted on 173 adolescent respondents on antiretroviral therapy who were selected using a systematic random sampling method. Data was collected using the questionnaires with the adopted Morisky drug adherence scale and analyzed using Statistical Package for the Social Sciences software, version 20. Chi square, fishers' exact statistical tests and the binary logistic regression model were used to determine true predictors and to adjust confounders of adherence. The cut off point for statistical significance was set at 5%. Results: This study established that 76 (43.9%) of the respondents were non-adherent to their antiretroviral therapy. Knowledge of HIV and disease progression was reported to be low but had no statistical impact on antiretroviral therapy adherence. Stigmatization was high (99 (57.2%)) but did not significantly influence adherence to combination antiretroviral therapy on the study participants. Factors which were found to be statistically significant to adherence to therapy when a binary logistic regression was performed were experiencing side effects to therapy (p-value 0.047, odds ratio = 0.412); understanding reason for taking combination antiretroviral therapy (p-value 0.006, odds ratio = 5.978) and being reminded to take drugs (p-value 0.006, odds ratio = 0.505). Conclusion: The study found that there was high level of non-adherence to combination antiretroviral therapy which could subsequently lead to