Background <p>Breast cancer is the leading cause of cancer death in women in Morocco and worldwide. The development of anti-HER2 therapies has improved the management of HER2-positive breast cancers. However, cardiotoxicity remains the major complication observed in patients undergoing this treatment and genetic factors appear to be involved in the predisposition to these cardiovascular toxicities. The present systematic review aims to further elucidate the relationship between some genetic polymorphisms and cardiotoxicity in HER2-positive breast cancers.</p> Methods <p>All relevant studies, that investigated the association between genetic variants and cardiotoxicity in adult patients with HER2-positive breast cancer treated with anti-HER2 targeted therapy, have been extracted from PubMed, Scopus, and Google Scholar databases up to February 2025.</p> Results <p>15 studies were enrolled after strict literature screening. Most of them have analyzed <i>HER2</i> gene polymorphisms, which are most likely associated with cardiotoxicity induced by anti-HER2 treatments; nevertheless, some findings are still inconclusive.</p> Conclusion <p>The current evidence does not yet justify clinical implementation of <i>HER2</i> polymorphism testing. Larger studies such as multi-center cohorts including biomarkers and pharmacokinetic data are needed to confirm the effects of these genetic variants in predicting cardiotoxicity in patients with HER2-positive breast cancer.</p>