Background: Frailty is characterized by a progressive decline in the physiological functions of multiple body systems that lead to a more vulnerable condition, which is prone to the development of various adverse events, such as falls, hospitalization, and mortality. This study aims to determine whether frailty increases mortality compared to pre-frailty and to identify variables associated with a higher risk of mortality. Materials: Two cohorts, frail and pre-frail subjects, are evaluated according to the Fried phenotype. A complete examination of frailty, cognitive status, comorbidities and pharmacology was carried out at hospital admission and was extracted through electronic health record (EHR). Mortality was evaluated from the EHR. Methods: Kaplan–Meier estimates of survival probability functions were calculated at two years censoring time for frail and pre-frail cohorts. The log-rank test assessed significant differences between survival probability functions. Significant variables for frailty (p< 0–05) were extracted by independent samplet-test. Further selection was based on variable significance found in multivariate logistic regression discrimination between frail and pre-frail subjects. Cox regression over univariatet-test-selected variables was calculated to identify variables associated with higher proportional hazard risks (HR) at two years. Results: Frailty is associated with greater mortality at two years censoring time than pre-frailty (log-rank test,p< 0.0001). Variables with significant (p< 0.05) association with mortality identified in both cohorts (HR 95% (CI in the frail cohort) are male sex (0.44 (0.29–0.66)), age (1.05 (1.01–1.09)), weight (0.98 (0.96–1.00)), and use of proton-pump inhibitors (PPIs) (0.60 (0.41–0.87)). Specific high-risk factors in the frail cohort are readmission at 30 days (0.50 (0.33–0.74)), SPPB sit and stand (0.62 (0.45–0.85)), heart failure (0.67 (0.46–0.98)), use of antiplatelets (1.80 (1.19–2.71)), and quetiapine (0.31 (0.12–0.81)). Specific high-risk factors in the pre-frail cohort are Barthel’s score (120 (7.7–1700)), Pfeiffer test (8.4; (2.3–31)), Mini Nutritional Assessment (MNA) (1200 (18–88,000)), constipation (0.025 (0.0027–0.24)), falls (18,000 (150–2,200,000)), deep venous thrombosis (8400 (19–3,700,000)), cerebrovascular disease (0.01 (0.00064–0.16)), diabetes (360 (3.4–39,000)), thyroid disease (0.00099 (0.000012–0.085)), and the use of PPIs (0.062 (0.0072–0.54)), Zolpidem (0.000014 (0.0000000021–0.092)), antidiabetics (0.00015 (0.00000042–0.051)), diuretics (0.0003 (0.000004–0.022)), and opiates (0.000069 (0.00000035–0.013)). Conclusions: Frailty is associated with higher mortality at two years than pre-frailty. Frailty is recognized as a systemic syndrome with many links to older-age comorbidities, which are also found in our study. Polypharmacy is strongly associated with frailty, and several commonly prescribed drugs are strongly associated with increased mortality. It must be considered that frail patients need coordinated attention where the diverse specialist taking care of them jointly examines the interactions between the diversity of treatments prescribed.