Background/Objectives: Venlafaxine (VEN) is a serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant. Arterial hypertension (HTN), heart failure (HF), and arrhythmias are side effects of VEN. Cardiotoxicity (CTOX) as a feature of VEN-associated side-effects has only rarely been described. Methods: We conducted a search of our database for cases of VEN-associated CTOX, analyzing symptoms, echocardiographic findings, and laboratory results. Results: We identified five patients (three females, two males) with VEN-associated CTOX, aged 51 to 87 years at presentation. VEN dose was 150 and 375 mg daily and treatment duration was 1.5 to 15 years. Presenting features were HTN in three, “hypertrophic cardiomyopathy” in two, heart failure in three, and atrial fibrillation in three patients. Symptoms and signs of CTOX were reversible in all patients after discontinuation or dose reduction of VEN, suggesting a causal relationship between VEN and CTOX. Conclusions: VEN-associated CTOX can occur and progress to severe cardiomyopathy or heart failure. Potential risk factors include cardiac sympathetic stimulation, high VEN dosage, and prolonged treatment duration; however, CTOX may also occur at standard doses. Therefore, patients taking VEN should be routinely monitored for signs of cardiotoxicity, including monitoring of serum concentrations of VEN.