BackgroundPoor clinical adherence is the main factor that hinders ART adherence level in children and its ultimate effect on viral load suppression and decreasing morbidity and mortality of children. Although data from different settings are necessary to tackle such types of problems, the pieces of evidence are limited in the case of clinical adherence level. Therefore, this study was intended to assess clinical non-adherence and its associated factors among HIV-infected pediatrics on highly active antiretroviral therapy.MethodsA multi-center cross-sectional study was conducted from July 1 to August 30, 2021, among HIV-infected children receiving ART in the South Gondar Zone. Data were collected through face-to-face interviews, and reviewing patients’ documents using a structured checklist. Data were entered into Epi-data version 4.6 and exported to the Statistical Package for Social Science version 23 for analysis. Binary logistic regression was used to assess the association between the factors and the outcome variable. The significance of variables was declared when a p-value was less than 0.05.ResultsFrom 422 participants, 383 have involved in the study making the response rate of 90.7%. Almost half of the study participants 190 (49.6%) were girls. Two hundred ninety-one (76%) of caretakers were biological mothers, and 203 (53%) did not have adherence supporters. About 179 (46.7%) of caretakers did not disclose the status of the child about the illness. The overall prevalence of non-adherence among children on ART was 31.9% (95% CI: 27.2–36.6). Rural residency, diagnostic status non-disclosure, no adherence supporter, having no biological caretaker and co-morbid illness were significantly associated with clinical non-adherence of HIV positive children.ConclusionClinical non-adherence among children among HIV-positive children attending care in south Gondar zone health facilities is unacceptably high. Attention shall be given to HIV-positive pediatrics who reside in rural areas, whose status was not disclosed, had no adherence supporter, had a non-biological caretaker, and had comorbidity to have good clinical adherence on ART service.