Background <p>Sepsis and septic shock are associated with high ICU mortality, and early risk stratification remains challenging. We assessed whether admission serum interleukin-6 (IL-6), neuropilin-1 (Nrp-1), and amphiregulin (AREG) predict 28- and 90-day mortality in ICU patients meeting Sepsis-3 criteria.</p> Methods <p>In this prospective single-center observational study, 100 adults with sepsis (<i>n</i> = 59) or septic shock (<i>n</i> = 41) were enrolled; 60 healthy volunteers provided exploratory reference values only. Serum IL-6, Nrp-1, and AREG were measured by ELISA within 24&#xa0;h of ICU admission. The primary outcomes were 28-day and 90-day mortality. Discrimination was assessed with receiver operating characteristic (ROC) analysis and cut-offs were derived using the Youden index. Multivariable logistic regression was used to identify independent predictors of 90-day mortality.</p> Results <p>Admission Nrp-1 was higher in non-survivors at both 28 and 90 days and showed modest discrimination (AUC 0.650 and 0.627, respectively). Youden cut-offs were 235 pg/mL for 28-day mortality and 165 pg/mL for 90-day mortality. In multivariable analysis, Nrp-1 (aOR 1.004 per 1 pg/mL; ~1.49 per 100 pg/mL), age, SOFA score, and non-urogenital infection focus were independently associated with 90-day mortality; the combined model demonstrated moderate discrimination (AUC 0.793). IL-6 and AREG were not associated with 28-day or 90-day mortality.</p> Conclusions <p>Admission Nrp-1 may provide adjunct prognostic information but its standalone performance is modest; it should be interpreted alongside established clinical risk scores. External validation in larger multicenter cohorts, preferably with serial measurements, is warranted.</p> Clinical trial number <p>Not applicable.</p>