Objective: To provide an updated and expanded analysis of clinical outcome and immunohistochemical (IHC) findings unique to primary dermal melanoma (PDM) that may be used to differentiate this entity from primary nodular melanoma (PNM) and cutaneous metastatic melanoma (MM). Design: Cohort analysis and extensive IHC panel comparing PDM with PNM and cutaneous MM. Setting: Melanoma clinics and pathology departments of academic and VA medical centers. Patients: Thirteen patients with a solitary dermal or subcutaneous nodule of histologically proven melanoma, prospectively followed through April 30, 2007. Interventions: Clinical, pathologic, and IHC assessment of patients diagnosed as having PDM. Main Outcome Measures: Long-term clinical outcome and determination of unique clinical and IHC features in the study cohort compared with other melanoma subtypes. Results: Histologically, there was no evidence of an overlying in situ component, ulceration, or regression, and there was no associated nevus in any cases. Clinical history and findings from workup, including imaging studies, skin examination, and sentinel lymph node biopsy, were negative for evidence of melanoma elsewhere. The mean Breslow depth was 9.6 mm. Two patients developed satellite or in-transit recurrences, 1 developed pulmonary metastasis, and another died of liver metastases. Overall, the cohort showed a 92% melanoma-specific survival rate at a mean duration of follow-up of 44 months. The IHC findings showed that PDM exhibited lower levels of staining for the antigens p53 (P=.02), Ki-67 (Mib-1) (P=.002), cyclin D1 (P=.001), and podoplanin (recognized by D2-40 antibody) lymphovascular staining (P<.001) compared with MM and PNM. All other markers were comparable. Conclusions: Patients with PDM have remarkably prolonged survival compared with patients with MM or PNM of similar thickness. Preliminary results suggest that PDM may be characterized by lower levels of p53, Ki-67, cyclin D1, and D2-40 compared with histologically similar MM and PNM.