Understanding the nature and clinical relevance of non-neurological complications is crucial to provide an appropriate management to patients with acute stroke. The aims of this study in patients with acute stroke were to assess the in-hospital frequency of non-neurological complications and the correlation between these complications and adverse outcome (death or disability) at 3 months. Patients with acute ischemic or hemorrhagic stroke admitted to the Stroke Unit of the University of Perugia were included in a prospective cohort study. Pre-defined non-neurological complications were considered for study purposes. Study outcomes were 3-month death and composite of death and disability. Stroke was defined as not disabling (mRS 0-2) or disabling (mRS 3-5) or leading to death (mRS 6). Multiple logistic regression analysis was used to identify predictors for study outcomes. 1,101 consecutive patients (mean age 72.2 ± 13.1 years; 57.1% males; 926 ischemic and 175 hemorrhagic) were included in the study; 338 patients (30.7%) experienced at least one non-neurological complication. 269 patients (24.4%) had fever, 210 patients (19.1%) infection in one or more sites, 86 patients (7.8%) venous thromboembolism (VTE) and 34 patients (3.0%) myocardial infarction. At 3 months, 511 patients (46.4%) were disabled and 123 had died (11.2%). Regression logistic analysis found that: (1) age (OR 1.06 for 1 added year; 95% CI 1.03-1.08), NIHSS score on admission (OR 1.31 for 1 added point; 95% CI 1.25-1.38), current smoking (OR 1.92; 95% CI 1.08-3.39), infection in any site (OR 4.13; 95% CI 1.51-11.28) and VTE (OR 6.03; 95% CI 1.44-25.11) were associated with death and/or disability (mRS ≥ 3) and that (2) age (OR 1.06 for 1 added year; 95% CI 1.02-1.09), high NIHSS score on admission (OR 1.21 for 1 added point; 95% CI 1.15-1.27), male gender (OR 1.93; 95% CI 1.04-3.62), fever (OR 2.29; 95% CI 1.08-4.86) and myocardial infarction (OR 6.57; 95% CI 2.30-18.74) were associated with increased mortality. In conclusions, patients with acute stroke are at high risk of non-neurological complications, such as fever with or without infections, venous thromboembolism and myocardial infarction. Non-neurological complications are associated with increased long-term disability and death.