Background: COVID-19 caused a high level of morbidity and mortality. All age groups are at risk to acquire infection, especially chronically-ill patients; however, there is a hesitancy toward vaccines among them. Aim of the work: The study aims to assess the prevalence of Covid-19 vaccine hesitancy and to identify the underlying factors among chronically-ill patients. Methods: An analytical cross-sectional study was conducted at the outpatient clinics of the Internal Medicine Department at Kasr Al-Ainy Medical school. A self-administered Arabic questionnaire was distributed by the researchers to the patients surveying the acceptance rate of vaccination. Results: A total of 587 participants ruled in the study, and their response rate was 78.2 %. The prevalence of COVID-19 Vaccine hesitancy was 29.8%, and the main underlying causes of vaccine hesitancy were fear of the complications of vaccination and fear of the deterioration of chronic diseases (36.4% & 25.5 %) respectively. A statistical significance was detected between vaccine hesitancy and many factors such as (gender, educational level, smoking status, type of chronic disease, and attitude toward the safety of vaccine) P ≤ 0.001. Multiple logistic regression models yielded that significant predictors for vaccine hesitancy were females (OR 2.119), Illiterate (OR 1.73), not working in medical field (OR 2.311), using sources of knowledge other than Ministry of Health Website (OR 3.716), non Hypertensive (OR 1.45), having autoimmune diseases (OR1.68). Conclusions: Relatively significant Covid-19 vaccine hesitancy among chronically-ill patients is influenced by gender, educational level, smoking status, attitude toward safety of vaccine, and source of knowledge regarding the vaccine.