The role of the apolipoprotein E (APOE) and the angiotensin converting enzyme (ACE) polymorphisms on health and functional status deterioration in old age is still undefined. Recently, a Multidimensional Prognostic Index (MPI) for 1-year mortality derived from a Comprehensive Geriatric Assessment (CGA) was developed and validated in hospitalized elderly patients. The aim of this study was to investigate the possible association of the APOE and ACE gene polymorphisms with the multidimensional impairment, as evaluated by the MPI, in older patients. These polymorphisms were assessed in 1894 geriatric inpatients divided into three groups according to their MPI values: MPI-1 low risk (n = 988), MPI-2 moderate risk (n = 671), and MPI-3 severe risk of mortality (n = 235). A slight deviation from Hardy-Weinberg equilibrium was observed for the APOE genotypes. With the increasing of the MPI grade, a significant increase in the frequencies of epsilon4 allele and the ACE D/D genotype was observed. The APOE epsilon4(+) and ACE D/D genotypes were associated with severe MPI grade (APOE epsilon4(+), odds ration [OR] = 1.79, 95% confidence interval [CI] 1.20-2.67; ACE D/D, OR = 1.42, 95% CI 1.05-1.92). The combined APOE epsilon4(+) and ACE D/D genetic status was associated with higher MPI grade (OR = 2.85, 95% CI 1.75-4.65), without interaction. No significant associations between APOE and ACE polymorphisms and 2-year mortality were found. APOE and ACE genes might predispose individuals to health and functional status deterioration in old age, and their effect is additive.