Isotretinoin (ISO) is a synthetic retinoid approved for the treatment of acne vulgaris. Despite satisfactory results, it is still controversial due to numerous adverse events (AE). However, there is a lack of literature examining the factors affecting the frequency and severity of these AEs. Lifestyle patterns may have an impact as they have the greatest impact on a person’s overall health. The aim of the research is to evaluate the impact of lifestyle patterns on the occurrence and severity of systemic ISO AEs in patients suffering from acne. A retrospective cohort study was conducted using a database of collected information about adults diagnosed with acne and treated with systemic ISO. Patients were divided into several groups according to their smoking status (nonsmokers, smokers), BMI (normal weight, overweight), physical activity (active, inactive), and compliance with the Mediterranean diet (adherent, not adherent). Considering all mentioned lifestyle factors, responders were categorized into healthy and unhealthy lifestyle groups. 124 adults with acne, undergoing systemic ISO therapy, made up the study group. There were generally no significant differences in patient characteristics across groups (P > 0.05). Almost all classes and subclasses of AEs showed no significant differences in groups (P > 0.05). ISO is still the most effective drug in the treatment of acne and despite the AEs, therapy should not be abandoned. Moreover, lifestyle factors such as physical activity, smoking, and eating habits do not affect the incidence and severity of AEs, which proves the safety of ISO regardless of unhealthy habits.