Background:Hydroxychloroquine (HCQ) is widely used to manage autoimmune conditions such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren's syndrome. However, HCQ can cause cardiotoxicity, a dose-dependent complication linked to the accumulation of metabolites in lysosomes that alters cellular pH. HCQ-induced cardiotoxicity can lead to various cardiac abnormalities, including conduction defects, hypertrophy, and heart failure (HF). Importantly, this toxicity may be reversible with early detection and prompt discontinuation of HCQ.Case Summary:Three cases of SLE patients with prolonged HCQ use are presented, all of whom exhibited signs of cardiomyopathy and HF. The first case involved a 70-year-old male with a 30-year history of HCQ use, who presented with Mobitz II A-V block and other cardiac abnormalities. The second case was a 45-year-old female with a 26-year history of HCQ therapy who developed sinus tachycardia and biatrial enlargement. The third case involved a 75-year-old woman with 30 years of HCQ use, presenting with shortness of breath and pulmonary hypertension. In all cases, HCQ was discontinued, and supportive HF therapy was initiated, leading to improved ejection fraction and resolution of symptoms within months.Discussion:HCQ cardiotoxicity, although rare, is an important consideration in patients on long-term therapy, particularly as it is potentially reversible. The diagnosis can be challenging due to the nonspecific nature of cardiac symptoms and overlaps with other conditions. Imaging, particularly cardiac magnetic resonance imaging, plays a crucial role in early detection, while endomyocardial biopsy provides a definitive diagnosis. These cases underscore the need for clinicians to be aware of HCQ cardiotoxicity, as early intervention can improve patient outcomes.