Pneumonia is the leading infection-related cause of death. The use of simple clinical criteria and contemporary epidemiology to identify patients at high risk of nosocomial pneumonia should enhance prevention efforts and facilitate development of new treatments in clinical trials. What are the clinical criteria and contemporary epidemiology trends that are helpful in the identification of patients at high risk of nosocomial pneumonia? Within the ICUs of 28 US hospitals, we conducted a prospective cohort study among adults who had been hospitalized >48 hours and were considered high risk for pneumonia (defined as treatment with invasive or noninvasive ventilatory support or high levels of supplemental oxygen). We estimated the proportion of high-risk patients who experienced the development of nosocomial pneumonia. Using multivariable logistic regression, we identified patient characteristics and treatment exposures that are associated with increased risk of pneumonia development during the ICU admission. Between February 6, 2016, and October 7, 2016, 4,613 high-risk patients were enrolled. Among 1,464 high-risk patients (32%) who were treated for possible nosocomial pneumonia, 537 (37%) met the study pneumonia definition. Among high-risk patients, a multivariable logistic model was developed to identify key patient characteristics and treatment exposures that are associated with increased risk of nosocomial pneumonia development (c-statistic, 0.709; 95% CI, 0.686-0.731). Key factors associated with increased odds of nosocomial pneumonia included an admission diagnosis of trauma or cerebrovascular accident, receipt of enteral nutrition, documented aspiration risk, and receipt of systemic antibacterials within the preceding 90 days. Treatment for nosocomial pneumonia is common among patients in the ICU who are receiving high levels of respiratory support, yet more than one-half of patients who are treated do not fulfill standard diagnostic criteria for pneumonia. Application of simple clinical criteria may improve the feasibility of clinical trials of pneumonia prevention and treatment by facilitating prospective identification of patients at highest risk.