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Background: Mucosal Leishmaniasis (ML), a neglected tropical disease caused by Leishmania parasites, impairs the quality of life of under-resourced populations in South America. If not treated promptly, this disease progresses to facial deformities and death. The low sensitivity of microscopy results and the unavailability of other accurate tests hamper the diagnosis. As clinical criteria are readily available in any setting, these may be combined in a syndromic algorithm, which in turn can be used as a diagnostic tool. We explore potential clinical criteria for a syndromic diagnostic algorithm for ML in rural healthcare settings in South America. Methodology/Principal findings: The protocol for this systematic review was pre-registered in PROSPERO with the number: CRD42017074148. In patients with ML, described in case series identified through a systematic retrieval process, we explored the cumulative ML detection rates of clinical criteria. Participants: all patients with active mucosal disease from an endemic area in South America. Any original, non-treatment study was eligible, and case reports were excluded. PUBMED, EMBASE, Web of Science, SCIELO, and LILACS databases were searched without restrictions. The risk of bias was assessed with the JBI checklist for case series. We included 10 full texts describing 192 ML patients. Male gender had the highest detection rate (88%), followed by ulcer of the nasal mucosa (77%), age >15 (69%), and symptom duration >4 months (63%). Significance: Within this selection of patients, we found that the male gender, ulcer of the nasal mucosa, age >15, and symptom duration >4 months lead to the highest detection rates. However, higher detection comes -naturally- with a higher rate of false positives as well. As we only included ML patients, this could not be verified. Therefore, the criteria that we found to be most promising should be validated in a well-designed prospective study. Author summary: Mucosal leishmaniasis, a disease caused by Leishmania parasites, is transmitted from animals to humans by sandflies. It is a forgotten disease that affects under-resourced populations in South America. Without treatment, this disease mutilates the face and can even be fatal. Diagnosing mucosal leishmaniasis is challenging. The only available testing in rural areas is the use of either a lesion smear or biopsy for light microscopy, however, this is unreliable. Many patients suffer for years before receiving treatment. Syndromic algorithms use patient characteristics, such as age, gender, and symptoms to identify patients for treatment. This method has been promoted to manage infectious diseases, such as tuberculosis and sexually transmitted diseases, in low resource settings. We explore clinical criteria for a new algorithm to diagnose mucosal leishmaniasis in patients described in the medical literature. We searched the literature for reports written in any language and identified 10 studies describing 192 patients with mucosal leishmaniasis. We found that male gender, ulcer of the nasal mucosa, age >15, and symptom duration >4 months lead to acceptable detection rates. Therefore, diagnostic algorithms might improve the detection of patients with mucosal leishmaniasis but need prospective studies in clinical practice to prove their true potential. [ABSTRACT FROM AUTHOR]