Background An increasing number of patients with acute respiratory failure are supported with noninvasive ventilation (NIV). Although one-third of the patients receiving NIV experience delirium, its cause largely is unknown. It is hypothesized that frailty may be a contributing factor. Research Question Does delirium have an association with hospital mortality in patients with and without frailty receiving only NIV? Study Design and Methods This was a retrospective, multicenter registry-based observational study using the Australian and New Zealand Intensive Care Society Adult Patient Database. All adults (aged ≥ 16 years) with critical illness across 178 ICUs between January 1, 2018, and December 31, 2022, with a documented clinical frailty scale score requiring NIV were included. The primary outcome was hospital mortality. We assessed the association between delirium and hospital mortality in patients with and without frailty, adjusting for acute illness severity at ICU admission, sex, hospital type, unplanned ICU admission, and if ICU admission happened after rapid response team review. Results We included 30,534 patients, of whom 12,872 patients (42.2%) were frail. Delirium was more prevalent in patients with frailty (10.0% vs 5.6%; P < .001). The in-hospital mortality was higher in patients with frailty (22.5% vs 9.0%; P < .001) when compared with those without frailty. Delirium was associated independently with higher mortality across all patients, regardless of the frailty status (33.2% vs 21.0%; adjusted OR [aOR], 1.59; 95% CI, 1.40-1.80). Furthermore, delirium was associated with smaller increases in hospital mortality in patients with frailty (aOR, 1.42; 95% CI, 1.22-1.66) compared with those without frailty (aOR, 1.90; 95% CI, 1.53-2.35). Interpretation Although delirium was associated with higher hospital mortality, the relative impact of this association was greatest in patients without frailty. These findings challenge the 1-size-fits-all approach to delirium management in the ICU, advocating for nuanced strategies that consider the broader clinical context, including frailty.