Background <p>Periprosthetic femoral fractures (PFF) occur predominantly in older, frail patients and are associated with substantial mortality. While age, comorbidity, and frailty are established predictors of adverse outcomes, the prognostic value of systemic inflammatory markers in PFF remains unclear. This study aimed to identify independent predictors of 24-month mortality following PFF and to evaluate whether the Systemic Immune-Inflammatory Index (SII) is associated with mortality after adjustment for established clinical risk factors.</p> Methods <p>A retrospective cohort study was conducted including 186 consecutive patients admitted with PFF between 2019 and 2023. The primary outcome was all-cause mortality within 24 months. Cox proportional hazards regression was used to identify predictors of mortality. Model discrimination was assessed using Harrell’s C-index and internally validated with bootstrap resampling (1000 iterations).</p> Results <p>During 24-month follow-up, 55 patients died (29.6%). In multivariable analysis, age (HR 1.06 per year; 95% CI 1.02–1.11; <i>p</i> = 0.003), male sex (HR 2.23; 95% CI 1.27–3.93; <i>p</i> = 0.006), and frailty (Clinical Frailty Scale; HR 1.69 per unit; 95% CI 1.35–2.11; <i>p</i> &lt; 0.001) were independently associated with mortality. SII/100 remained independently associated with mortality after adjustment (HR 1.02; 95% CI 1.00–1.04; <i>p</i> = 0.027). Model discrimination was good (C-index 0.769), with minimal optimism after internal validation (corrected C-index 0.759).</p> Conclusions <p>Two-year mortality after PFF is primarily associated with patient-related vulnerability factors, including age, sex, and frailty. SII was independently associated with mortality after adjustment for established clinical predictors. However, the incremental improvement in model discrimination was modest, and further studies are required to determine its clinical utility and potential role in prognostic modelling.</p>