Background: Upper Respiratory Tract Infections (ISPA) are among the conditions frequently encountered in healthcare settings. Inappropriate antibiotic use can lead to patient non-adherence to therapy and increase the risk of antibiotic resistance. A patient’s level of knowledge regarding antibiotic use is believed to be associated with treatment adherence. Objective: This study aims to determine the relationship between the level of knowledge and the adherence of patients with Upper Respiratory Tract Infections (ISPA) regarding antibiotic use at the Sawah Lebar Community Health Center in Bengkulu City. Method: The study employed a cross-sectional design with a prospective approach. The sample consisted of 100 patients with upper respiratory tract infections (ISPA), selected using purposive sampling. Data were collected via questionnaires assessing knowledge (15 questions) and adherence (8 questions), both of which had undergone validity and reliability testing. Data analysis was conducted using univariate and bivariate methods, specifically the Chi-Square test via SPSS. Result: The study results indicate a significant relationship between the level of knowledge and patient adherence regarding antibiotic use p=0,000, X²=39,555, with a Contingency Coefficient of C=0,532, indicating a relationship of moderate to strong strength. Conclusion: There is a significant relationship between the level of knowledge and the adherence of patients with upper respiratory tract infections (ISPA) regarding antibiotic use at the Sawah Lebar Community Health Center in Bengkulu City. The better the patients' level of knowledge, the greater their tendency to adhere to proper antibiotic use.