Background: This study aims to evaluate the prognostic role of serum PCT in older patients with suspect sepsis or infective diagnosis in the Emergency Department (ED) with a particular focus on the clinical consequences and characteristics due to frailty status. Methods: This is a observational retrospective study conducted in the ED of a teaching hospital. We identified all consecutive patients aged ≥ 80 years admitted to the ED and subsequently hospitalized for clinical suspicion of infection. Inclusion criteria were: age ≥ 80 years and clinical suspicion of infection; availability of a PCT determination obtained < 24 h since ED access; and Clinical Frailty Scale (CFS) determination. Study endpoints were the diagnostic accuracy of PCT for all-cause in-hospital death, infective diagnosis at discharge, and bloodstream infection. Diagnostic accuracy was calculated via ROC analysis and compared in the patients with severe frailty, measured by CFS > 6, and patients with low or moderate frailty (CFS 1–6). A multivariate analysis was performed to calculate the adjusted odds of raised PCT values for the study endpoints. Results: In total, 1459 adults ≥ 80 years with a clinical suspicion of infection were included in the study cohort. The median age of the sample was 85 years (82–89), with 718 (49.2%) males. The multivariate models revealed that, after adjusting for significant covariates, the PCT values at ED admission were significantly associated with higher odds of infective diagnosis only in the fit/moderately frail group (Odds Ratio [95% CI] 1.04 [1.01–1.08],p0.009) and not in very frail patients (Odds Ratio [95% CI] 1.02 [0.99–1.06],p0.130). Similarly, PCT values were significantly associated with higher odds of in-hospital death in the fit/moderately frail group (Odds Ratio [95% CI] 1.01 [1.00–1.02],p0.047), but not in the very frail ones (Odds Ratio [95% CI] 1.00 [0.98–1.02],p0.948). Conversely, the PCT values were confirmed to be a good independent predictor of bloodstream infection in both the fit/moderately frail group (Odds Ratio [95% CI] 1.06 [1.04–1.08],p< 0.001) and the very frail group (Odds Ratio [95% CI] 1.05 [1.03–1.07],p< 0.001). Conclusions: The PCT values at ED admission do not predict infective diagnosis, nor are associated with higher odds of in-hospital death. Still, in frail older adults, the PCT values in ED could be a useful predictor of bloodstream infection.