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Simple Summary: In the era of precision medicine, translational oncology seeks to identify new, targeted therapies for tumors with rare genetic mutations. Patients receiving targeted therapy are known to have better outcomes (i.e., live longer and better) compared to those receiving non-targeted therapies. In this analysis, we retrospectively analyzed 63,873 tumor tissues to better understand the rare HRAS mutation. We found that only 0.8% of tumors are HRAS mutant, and these tumors look different at the molecular level and behave differently on a clinical level. Targeted therapies for patients with HRAS mutations, such as tipifarnib, currently exist and are being tested in various tumor types. Our study seeks to add to the limited information currently known about this rare genetic mutation. Tipifarnib is the only targeted therapy breakthrough for HRAS-mutant (HRASmt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The molecular profiles of HRASmt cancers are difficult to explore given the low frequency of HRASmt. This study aims to understand the molecular co-alterations, immune profiles, and clinical outcomes of 524 HRASmt solid tumors including urothelial carcinoma (UC), breast cancer (BC), non-small-cell lung cancer (NSCLC), melanoma, and HNSCC. HRASmt was most common in UC (3.0%), followed by HNSCC (2.82%), melanoma (1.05%), BC (0.45%), and NSCLC (0.44%). HRASmt was absent in Her2+ BC regardless of hormone receptor status. HRASmt was more frequently associated with squamous compared to non-squamous NSCLC (60% vs. 40% in HRASwt, p = 0.002). The tumor microenvironment (TME) of HRASmt demonstrated increased M1 macrophages in triple-negative BC (TNBC), HNSCC, squamous NSCLC, and UC; increased M2 macrophages in TNBC; and increased CD8+ T-cells in HNSCC (all p < 0.05). Finally, HRASmt was associated with shorter overall survival in HNSCC (HR: 1.564, CI: 1.16–2.11, p = 0.003) but not in the other cancer types examined. In conclusion, this study provides new insights into the unique molecular profiles of HRASmt tumors that may help to identify new targets and guide future clinical trial design. [ABSTRACT FROM AUTHOR]