Background: Pyoderma gangrenosum after cardiac surgery is a rare, noninfectious ulcerating skin disease mimicking sternal wound infection. Methods: A systematic search of literature for pyoderma gangrenosum complicating cases of cardiac surgerywas conducted between September 1985 and September 2020 on PubMed and Cochrane databases. A systematic review and detailed overview of clinical presentation, diagnostic, treatment, and outcome is provided. Results: A total of 15 studies enclosing 15 patients suffering from pyoderma gangrenosum following cardiac surgery were identified. Onset of symptoms was observed after a median of 5 days. Patients were predominantly male (81.3%) with a median age of 64 years. Typical clinical presentation mimicked sternal site infection, mainly by means of mediastinitis. Specific signs were rapid progression, erythematous to violaceous color of the wound border, accompanied by unspecific symptoms including fever, malaise, and severe pain. Additionally, pathergy (development of ulcers at the sites of minor cutaneous trauma) was reported frequently. Biopsy is mandatory with a cutaneous neutrophilic inflammation confirming the diagnosis. Initial treatment mostly (75.0% of reported cases) was misled, addressing suspicion of surgical site infection. After correct diagnosis, the treatment was switched to an immunosuppressive therapy. Full sternal wound closure took between 5 weeks and 5 months. Reported case mortality was 12.5% in actually low-risk surgeries. Conclusion: Despite pyoderma gangrenosum has typical signs, it remains an exclusion diagnosis. The treatment is completely opposite to the main differential diagnosis —the typical surgical site infection. Knowledge about diagnosis and treatment is essential in the context of avoiding fatal mistreatment.