Objective: Prodrome is defined by manifestations that precede a familial Mediterranean fever (FMF) attack and predict its emergence. We aimed to determine the frequency, characteristics, and clinical determinants of prodrome in patients with FMF. Method: This cross-sectional study was conducted in a tertiary rheumatology clinic. During the clinical interview, all patients completed a standardized questionnaire about the pre-attack period. Prodrome was defined as the presence of any recurrent pre-attack manifestation occurring at least 4 h before an attack. Patients were classified according to whether they had prodrome of any kind of attack. Results: The study enrolled 401 patients aged 37.7 +/- 11.0 years (mean +/- sd). Male gender, M694V/M694V, homozygous MEFV mutation, peritonitis, pleuritis, and arthritis were more frequent in prodrome-positive patients. Altogether, 141 patients (35.2%) had prodrome. Male gender and ever having attack types of peritonitis or arthritis were independent clinical determinants of prodrome [relative risk (95% confidence interval): 1.72 (1.07-2.76), p = 0.02; 4.27 (1.80-10.1), p = 0.001; 1.77 (1.04-3.04), p = 0.04, respectively]. Age, MEFV mutations, pleuritis, and erysipelas-like erythema were not clinical determinants. Conclusions: All FMF patients, particularly males and patients who had peritonitis or arthritis at any time, should be questioned about prodrome. Prodrome should be analysed in terms of elucidating the pathogenesis of FMF and as an opportunity for a secondary prevention strategy for impending attacks. This study may shed light on prodrome for future cytokine or drug studies with the purpose of developing new cost-effective treatment protocols irrespective of colchicine resistance.