Introduction: Malignant transformation of perineal fistulas in Crohn’s disease (CD) has rarely been reported in literature. We systematically reviewed all such cases of cancer reported since 1950 in order to further characterize this rare complication of CD. Methods: Ovid MEDLINE was searched for pertinent case reports using a combination of the keywords “fistula”, “cancer” and “Crohn’s disease”, and limited to the English language. Relevant results included both case series and individual case reports by 30 primary authors. The reference lists of the collected articles were also screened for further relevant citations. A patient of ours with similar diagnosis was also included in the series for review. All selected cases were then analyzed by age, gender, duration of CD and fistula, location of fistula, presenting symptoms, delay in diagnosis, method of diagnosis, histopathology and outcome.Results: In addition to our patient, literature review revealed 57 other cases of carcinomas associated with perineal fistulas in CD. The cohort contained 36 females and 22 males. The mean age at the diagnosis of cancer was 47.4 years for females and 52.9 years for males. Mean duration of CD prior to detection of cancer was 17.5 years in females and 24.8 years in males (p = 0.0008). Average duration of fistula prior to cancer transformation was 10 years for females and 20 years for males (p = 0.003). Adenocarcinoma was the most common histology (52%) followed by squamous cell carcinoma (36%). There was no difference in gender distribution for adenocarcinoma and squamous cell carcinoma. Patients mostly presented with complaints of pain (34.5%) while the most frequent finding on examination was an abscess (43%). On initial examination malignancy was suspected in only 24 % of patients. In 78% of patients the fistula was perianal or anorectal in location. Observed survival rate was 71% at 1 year and 61% at 2 years. Conclusion: Incidence of cancer in perineal fistulas of CD is rare compared to non-fistulous CD. Overall prognosis appears to be poor. Diagnosis can be often delayed due to non-specific symptoms and findings. While cancer appears to be associated with the duration of CD as well as fistula, this complication can present much earlier than anticipated. A high suspicion for malignancy in chronic perineal fistulas associated with CD should therefore be maintained in spite of negative biopsies. Especially in women, the shorter duration of CD and fistulas prior to malignant degeneration necessitates an aggressive approach to detect cancer at the earliest.