Abstract Purpose: Cutaneous melanoma is a significant public health concern with increasing incidence rates over the past three decades. While survival rates have improved, disparities exist among racial/ethnic groups and socioeconomic factors. Our objective was to explore the connection between survival rates of cutaneous melanoma and demographic/socioeconomic factors in New Mexico's varied population, particularly in rural vs. urban settings. Methods: This retrospective study utilized data from the New Mexico Tumor Registry (NMTR) within the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. A total of 3,979 cases of cutaneous melanoma diagnosed between 2010 and 2017 among New Mexico residents were analyzed based on specific ICDO-3 criteria. The impact of demographic characteristics, socioeconomic factors, and stage at diagnosis on melanoma-specific mortality was investigated. Cases with incomplete data or where melanoma was not the primary cancer were excluded. Survival differences were assessed using Kaplan-Meier methods and the Cox Proportional Hazards Model, with analyses conducted with a significance threshold set at P=0.05. Only histologically confirmed melanoma cases were included in the study. Results: In our analysis of 3,979 melanoma cases spanning 2010 to 2017, non-Hispanic whites (NHW) displayed the highest incidence (n = 3,617, P < 0.001). Conversely, Hispanic Whites (HW) and American Indians (AI) exhibited a higher likelihood of later-stage diagnoses, with 19.2% of American Indians diagnosed at stage 3, in contrast to 3.9% of NHW and 10.3% of Hispanic Whites (P < 0.001). Rural areas showed a propensity for advanced-stage diagnoses (P < 0.001), and diagnosis stage exhibited an inverse relationship with per capita income (P < 0.001). Increased mortality was observed among males, individuals over 50, and American Indians (all P <0.05). Rural American Indian or Hispanic patients had a hazard ratio of mortality at 0.37 (95% CI, 0.15-0.89). An overall decline in melanoma mortality post-2012, with a notable reduction after mid-2015 (P < 0.001), despite a slight increase in diagnoses from 529 in 2010 to 569 in 2017 (P = 0.034) was observed. Sensitivity analyses revealed that rural residence among AI/Hispanic individuals was associated with a lower risk of melanoma-specific mortality (HR 0.37, p = 0.026 in the inclusive analysis; HR 0.36, p = 0.025 in the exclusion of in-situ cases). Conclusions: Our study indicates rural residency is associated with more advanced melanoma diagnoses and lower income correlates with later-stage diagnoses. However, rural living may offer a protective effect against mortality for American Indian/Hispanic populations. Overall mortality has declined since 2012, contrasting with a slight rise in diagnoses. Citation Format: Yeojin Park, Aaron Segura, Lynn Midani, Barbara Gutierrez, Larimar I. Rodriguez, Charles Wiggins, Vernon S. Pankratz, John R. Durkin. Rural residence as a protective factor in melanoma mortality: Insights from a comprehensive analysis of 3,979 New Mexico cases (2010-2017) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 806.