Although response to colchicine has been proposed as one of the diagnostic criteria in patients with Familial Mediterranean fever (FMF), the validity of this response has not been validated. The aim of this study was to assess the efficacy of the response to colchicine and to evaluate the extent of the effect of placebo. A double-blind randomized placebo-controlled trial with a cross-over design was conducted. The frequency of FMF attacks, the disease score, physical examination, and acute phase reactants were assessed at 0, 3, and 6 months. Blood samples were collected for complete blood count (CBC), erythrocyte sedimentation rate (ESR), levels of serum C-reactive protein (CRP) and serum amyloid A (SAA), and MEFV mutation analysis in 79 patients with a preliminary diagnosis of FMF. Patients were randomly allocated to receive either drug A or drug B in a double-blind fashion. The designated drug was switched at 3 months. Patients taking colchicine had less frequent FMF attacks (median 0) and lower FMF disease score (median 0) when compared to those on placebo (median 1 and 3, respectively) (p = 0.002 and p = 0.007, respectively). In genetically confirmed FMF patients, median attack number and median disease score was 0 under colchicine treatment, whereas these parameters were significantly higher in the placebo group (median 2 and 8, respectively) (p = 0.007 and p = 0.02, respectively) suggesting that colchicine is more effective than placebo in reducing attacks and disease score. Positive and negative predictive values were 70.2 and 37.5 %, respectively. During the placebo period, patients had less FMF attacks when compared to that of the pre-study period (median 2 vs 6, respectively) (p < 0.001). The high false positive rate raises concerns for considering the colchicine response test as diagnostic for FMF. The role of placebo on the attacks of periodic fever syndromes needs to be further investigated.