Summary Background Little is known about the prevalence and impact of cognitive impairment in polypathological patients (PPs). Objectives To assess the prevalence of cognitive impairment (CI) and delirium, their associated risk factors, and their impact on survival of a multicenter population of PPs. Methods Prospective cohort study. Descriptive analysis of the prevalence, main clinical features of PPs with basal CI (by means of Short Portable Mental Status Questionnaire), and delirium (Confusion Assessment Method); and bivariate as well as multivariate assessment of the factors associated with both conditions. Survival analysis after 12 months follow-up by means of Kaplan–Meier curves, and multivariate analysis of mortality risk factors in PPs with CI, and those with delirium. Results CI was present in 39% [28% mild to moderate (3–7 errors), and 11% severe (≥ 8 errors)] of the 1434 PPs assessed [in the remaining 11% (n=198) delirium was detected]; only 26% of them had been previously diagnosed with dementia. One-year mortality was 46%/31.4% in those with/without CI [p<0.0001; relative risk (RR)=1.8 (1.5–2.3)]. Mean survival was 305±4/266±5 days in those with/without CI (p<0.0001). One-year mortality was 54.5%/34.8% in PPs with/without delirium, [p<0.0001, RR=2.25 (1.65–3)]. Mean survival after inclusion was 296±4/241±10 days in those with/without delirium (P<0.0001). Factors independently associated with mortality in PPs with CI were the presence of a concomitant active neoplasm [p=0.007; RR=3 (1.3–6.7)], severe dyspnea (p=0.04; RR=1.6 (1.02–2.6)], higher comorbidity load (p=0.003; RR=1.2 (1.07–1.4)], and ≥ 4 hospital admissions in the previous 12 months [p<0.0001; RR=5.2 (2.4–11.5)]. Factors associated with mortality in PPs with delirium were age ≥ 85 years [p=0.021, RR=2.3 (1.14–4.6)], chronic liver disease (p=0.019, RR=5.9 (1.3–25)], severe dyspnea [p=0.007; RR=2.7 (1.3–5.4)], plasma creatinine levels > 2mg/dL [p=0.003; RR=7.8 (2–26)], and polypharmacy [p=0.0019; RR=3.1 (1.2–8.1)]. Conclusion CI, as well as delirium, is common in PPs. Both play a deleterious role in 12-month survival. A systematic cognitive assessment as well as prevention and early detection of delirium should be included in the clinical care of all PPs.