Cancer represents important comorbidity, and data on outcomes are usually derived from selected oncologic units. Our aim was to evaluate possible sex-related differences and factors associated with in-hospital mortality (IHM) in a consecutive cohort of elderly patients with cancer admitted to internal medicine. We included all patients admitted to our department with a diagnosis of cancer during 2018. Based on the International Classification of Diseases, 9th Revision, Clinical Modification, demography, comorbidity burden, and diagnostic procedures were evaluated, with IHM as our outcome. We evaluated 955 subjects with cancer (23.9% of total hospital admissions), 42.9% were males, and the mean age was 76.4 ± 11.4 years. Metastatic cancer was diagnosed in 18.2%. The deceased group had a higher modified Elixhauser Index (17.6 ± 7.7 vs. 14 ± 7.3, p < 0.001), prevalence of cachexia (17.9% vs. 7.2%, p < 0.001), and presence of metastasis (27.8% vs. 16.3%, p = 0.001) than survivors. Females had a higher age (77.4 ± 11.4 vs. 75.5 ± 11.4, p = 0.013), and lower comorbidity (10.2 ± 5.9 vs. 12.0 ± 5.6, p < 0.001) than males. IHM was not significantly different among sex groups, but it was independently associated with cachexia and metastasis only in women. Comorbidities are highly prevalent in patients with cancer admitted to the internal medicine setting and are associated with an increased risk of all-cause mortality, especially in female elderly patients with advanced disease.