Purpose <p>Melanotic Neuroectodermal Tumor of Infancy (MNTI) is a rare, locally aggressive tumor with distinct pathological features and treatment paradigms commonly occurring in the head and neck region. Microscopically, it consists of a biphasic population of small neuroblast-like cells and larger melanin-containing epithelioid cells. The main purpose of this study is to characterize clinicopathological and immunohistochemical features of MNTI at a single institution and discuss challenges in the differential diagnosis.</p> Methods <p>We performed a retrospective analysis of MNTI cases diagnosed at our center during a 10-year period and discussed the differential diagnoses.</p> Results <p>Eleven MNTI cases were identified. Median patient age was 5 months. Male to Female ratio was 1.75:1. Tumor distribution was in the Maxilla (<i>n</i> = 8), Mandible (<i>n</i> = 1) greater wing of Sphenoid (<i>n</i> = 1), and Temporal bone (<i>n</i> = 1). All tumors revealed classic biphasic morphology in the resection specimens. By immunohistochemistry, 9/9 (100%) cases were positive for both AE1/AE3 and HMB45 in the larger epithelioid cells and 6/6 (100%) were positive for Synaptophysin in the smaller neuroblast-like cells. One patient had unique nested areas composed of mature glial tissue. One patient who had incomplete resection was given adjuvant radiotherapy. One patient developed a solitary ipsilateral lymph nodal metastasis. Follow-up period ranged from 1 to 93 months. All the patients were alive with no evidence of disease at the last follow-up (median: 16 months).</p> Conclusions <p>Lack of consideration of MNTI in the differential diagnosis can lead to misdiagnosis and undue exposure to cytotoxic therapies. Awareness of the classic biphasic morphology and distinct immunoprofile of MNTI is essential.</p>