Background: More than two million children are infected with HIV globally. Sub Saharan Africa bearing more than 90% of the global HIV burden. Adherence in children requires dedication of both the caregiver and the child to consistently follow treatment recommendations. Not only do patient and caregiver need to be committed to treatment, but a variety of other factors may complicate ART adherence in children. Study objective: To determine factors influencing adherence to antiretroviral therapy among HIV infected children receiving care at KCMC. Methodology: This was a hospital based analytical cross-sectional study. The study population were all HIV infected children aged 2 to 17years old. The study participants were obtained randomly using lottery method. Data was collected in the child centred family care clinic at KCMC. The study was conducted from October 2011 to April 2012. Structured questionnaire with close ended questions was developed and piloted at KCMC before final utilization. Three methods of collecting adherence data were used: first a two-day self report; second, one month self report; third, pill count from pharmacy pill as well as unannounced clinic pill counts. The collected data was processed and analyzed using SPSS version 16. Results: A total of 183 patients were enrolled, among them 92 (50.3%) were males and 91 (49.7%) were females. Most of patients 117 (63.9%) were adolescents (10-17 years) and were attending school 160 (87.4%).Of all the primary caregivers, 113 (61.7%) were biological parents and 70 (38.3%) were non biological parents. 154 (84.2%) caregivers employed and they had an average monthly income of above 100,000 TZS (50.3%). Patients who had good adherence were 148 (80.9%) according to two-day self report, 136(74.3%) by visual analogue scale and 64 (35.0%) by unannounced clinic pill count. Adherence level by all three methods of assessment showed only 45 (24.6%) patients had good adherence when subjected to all three measurements. Male patients were more likely to adhere to ARV drugs than females (80 (87.0%) vs 68 (74.8%) p value of 0.04. Patients who were using fixed dose combination of ARV drugs had better adherence as compared to those on unfixed combination drugs (OR 1.34 (0.62-3.08). Those patients who had not missed any ARV drug doses in six months time frame had good adherence with a p value of 0.012 and children who had not experienced drug side effects had better adherence than those who did experience side effects with a p value of 0.001. Children whose caregivers had an average monthly income above 100,000TZS with p value of 0.035, afforded transportation to clinic with p value of 0.001 and incurred other cost for additional food while child taking drugs with p value of 0.011, were more adherent to medication than those who do not. Conclusion: About 45 (24.0%) of patients had good adherence to ART when subjected to all three measures. ARV drug side effects, missing tablets in the previous months and household income are strong predictors of adherence to ART among HIV infected children. Recommendations: More than one measure of adherence should be used to increase their sensitivity because they complement each other. Every effort should be made to provide explanation of ARV drug side effects and how to manage. Adolescents need special peer counselling and support from the community is likely to improve adherence to ART among them.