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Abstract Background: Acute appendicitis in girls presenting with lower abdominal pain repre-sents a frequent diagnostic dilemma, given the overlap in clinical presentation with gynecological and non-surgical causes. This study aimed to evaluate the diagnostic performance of IL-6 and CD64 and to compare them with classical inflammatory markers and the Alvarado score. Methods: We conducted an observational case–control study over a three-year period (December 2022–December 2025) at the First University Paediatric Surgery Clinic (General Hospital of Thessaloniki “Georgios Gen-nimatas”). Consecutive girls aged ≤16 years presenting with lower abdominal pain were included. The primary outcome was the presence of appendicitis (yes/no), defined by the final clinical diagnosis and, where applicable, intraoperative and/or histo-pathological confirmation. Diagnostic performance was assessed using ROC curves/AUC with 95% confidence intervals estimated by the DeLong method. The prespecified primary model was a logistic regression including the Alvarado score and log1p(IL-6). Results: Of 74 initially assessed cases, one was excluded (appendiceal neuroendocrine tumour, NET G1), yielding a final sample of 73 girls: 37 with appendi-citis and 36 without appendicitis. IL-6 was higher in the appendicitis group (median 19.41 vs 4.10 pg/mL) and showed moderate discrimination (AUC 0.696). CRP showed lower/borderline performance (AUC 0.595), whereas CD64 did not demonstrate useful discrimination (AUC 0.521). The Alvarado score had the highest discriminatory ability (AUC 0.885). Adding IL-6 to the Alvarado score did not materially improve the AUC in the common subset. Conclusions: IL-6 demonstrates moderate diagnostic perfor-mance as a standalone biomarker and may be useful as an adjunct, particularly when a clinical score is unavailable or unreliable. CD64 did not add diagnostic information in this setting. Larger, prespecified studies are required to identify clinically useful cut-offs.