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Background: Familial Mediterranean fever (FMF) is the most prevalent inherited autoinflammatory disease worldwide. Ongoing subclinical inflammation, induces amyloidosis, even during the attack-free periods despite colchicine therapy. Serum calprotectin (CLP) belongs to the S100 protein family and was proposed as an indicator of inflammation in several diseases. Aim of the work: To evaluate serum calprotectin (CLP) levels among children with FMF during the attack-free periods. Patients and Methods: This cross-sectional case-control study included 35 children diagnosed with FMF in the attack-free period who were following at the Pediatric Rheumatology Outpatient Clinic, Children's Hospital, Faculty of Medicine Cairo University, and 35 children as a control group. This study was conducted during November 2020 to April 2021. Serum CLP was measured by ELISA. Results: The mean ± SD age of our studied FMF cohort was 9.23 ± 2.6 years; 15 (42.9%) were males, and 20 (57.1%) were females compared to the mean ± SD age of the control group 9.0 ± 2.6, 21 (60%) were males, and 14 (40%) were females(p=0.665 and p=0.151 respectively). The range of serum calprotectin levels among our FMF patients during the attack-free period was (15.4-1306) ng/ml, while the range in the control group, its range was (0.2 - 77) ng/ml with mean± SD was 24.62±16.66 ng/ml, (p-value = 0.001). Of those with FMF 25 (71.4%) had normal level of CLP (mean± SD= 31.6± 9.2 and range=15.4 – 48.6 ng/ml) and 10 (28.6%) had elevated CLP (mean± SD= 296.79±442.33 and range= 55 – 1306 ng/ml). There were no significant correlations between serum CLP levels and FMF clinical presentations, disease severity scores, different laboratory data, or types of MEFV gene mutation p- values = 0.697, 0.696 and 0.146 respectively. Conclusion: Serum CLP levels were elevated in a subset of children with FMF during the attack-free period. Serum CLP did not correlate with any studied parameter. The specificity and sensitivity of diagnostic accuracy and outcome prognostic ability of CLP in FMF remain to be studied.