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Background: Health literacy is the degree to which individuals have the capacity to obtain, process, and understand basic information on health services in order to make appropriate health decisions. The purpose of this study was to determine the effect of a health literacy educational program for the staff of health centers in Mashhad on promoting self-efficacy in patients with chronic diseases.Methods: This randomized clinical trial was conducted on 240 patients with chronic diseases in two experimental and control groups in pre-intervention and post-intervention stages. The participants were selected using multistage random sampling. The intervention was designed based on the 4 communication skills of speaking, writing, enabling, and improving support systems. The intervention was performed in 3 sessions of focus group discussions and a workshop for 12 personnel (doctors, nurses, dietitians, and disease experts) in the experimental group. The data collections tools consisted of the Health Literacy Assessment Questionnaire, Adult Primary Care Questionnaire, and Chronic Disease Self-Efficacy Scale. Data were analyzed using independent t-test, chi-square test, and ANOVA in SPSS software. The significance level in all tests was considered as less than 5%.Findings: The patients in the two groups did not differ significantly in terms of demographic variables before the intervention (P = 0.063). Significant differences were observed in personnel’s health literacy (P = 0.007), patients’ health literacy (P < 0.001), and patients’ self-efficacy (P = 0.003) in the experimental group after the intervention.Conclusion: Based on finding, educational interventions to improve the health literacy of staff are more effective on the improvement of patients’ self-efficacy in comparison with education programs provided in health centers.