Background: Primary malignant melanomas of the Gastrointestinal mucosa are uncommon. Most cases of gastrointestinal (GI) melanomas are secondary, arising from metastasis at distant sites. The purpose of this study is to assess to what extent the interaction between independent prognostic factors (age and tumor site) of primary GI melanoma influence survival. Furthermore, we also aimed to investigate the clinical characteristics, survival outcomes, and independent prognostic factors of patients with primary GI melanoma in the past decade. Methods: A total of 399 patients diagnosed with primary GI melanoma, between 2008 and 2017, were enrolled in our study by retrieving data from the Surveillance, Epidemiology, and End Results (SEER) database. We analyzed demographics, clinical characteristics, and overall mortality (OM) as well as cancer-specific mortality (CSM) of primary GI melanoma. Variables with apvalue < 0.1 in the univariate Cox regression were incorporated into the multivariate Cox model (model 1) to determine the independent prognostic factors, with a hazard ratio (HR) of greater than 1 representing adverse prognostic factors. Furthermore, we analyzed the effect of the interaction between age and primary location on mortality (model 2). Results: Multivariate cox proportional hazard regression analyses revealed higher OM in age group 80+ (HR = 5.653, 95% CI 2.212–14.445,p= 0), stomach location of the tumor (HR = 2.821, 95% CI 1.265–6.292,p= 0.011), regional lymph node involvement only (HR = 1.664, 95% CI 1.051–2.635,p< 0.05), regional involvement by both direct extension and lymph node involvement (HR = 1.755, 95% CI 1.047–2.943,p< 0.05) and distant metastases (HR = 4.491, 95% CI 3.115–6.476,p= 0), whereas the lowest OM was observed in patients with small intestine melanoma (HR = 0.383, 95% CI 0.173–0.846,p< 0.05). Multivariate cox proportional hazard regression analyses of CSM also revealed higher mortality of the same groups and lower CSM in small intestine and colon melanoma excluding the rectum. For model 2, considering the interaction between age and primary site on mortality, higher OM was found in age group 80+, followed by age group 40–59 then age group 60–79, regional lymph node involvement only, regional involvement by both direct extension and lymph node involvement and distant metastases. The small intestine had a lower OM. The rectum as primary location and the age range 40–59 interacted to lower the OM (HR = 0.14, 95% CI 0.02–0.89,p= 0.038). Age and primary gastric location did not interact to affect the OM. For the CSM, taking into account the interaction between age and the primary location, higher mortality was found in the same groups and the colon location. The primary colon location also interacted with the age group 40–59 to increase the CSM (HR = 1.38 × 109, 95% CI 7.80 × 107–2.45 × 1010,p= 0). Conclusions: In this United States population-based retrospective cohort study using the SEER database, we found that only the age range 40–59 interacted with the rectum and colon to lower and increase mortality respectively. Primary gastric location, which was the single most important location to affect mortality, did not interact with any age range to influence mortality. With those results, we hope to shed some light on this rare pathology with a very dismal prognosis.