Familial Mediterranean Fever (FMF) is characterized by recurrent acute attacks of fever and serositis, and colchicine is the primary treatment. The pathogenesis of the disease has not been fully understood. Resistance to colchicine remains to be a problem in up to 30% of the patients and yet there seems to be no alternative treatment. In this study our objective was to investigate whether a selective serotonin re-uptake inhibitor (SSRI) could affect the attack frequency and acute phase response in FMF patients who were unresponsive to colchicine. We retrospectively evaluated the hospital files of 11 colchicine-unresponsive FMF patients who had been treated with SSRIs. According to the records and re-evaluation of the patients, the total number of the FMF attacks was calculated before and after the SSRI, adjunct to colchicine. The laboratory values including erythrocyte sedimentation rate, C-reactive protein, fibrinogen and white blood cell counts were also noted before and after the SSRI treatment from their hospital files. The mean attack frequency before adding SSRI to colchicine was 8.09 ± 3.53 per 6 months, and at the end of this period there was a great decline in the number of mean attack frequency (0.36 ± 0.50 attacks per 6 months) (p < 0.001). Acute phase reactants were significantly decreased after SSRI treatment (p < 0.001). All of the colchicine-unresponsive patients had depression and 3 of those patients also had fibromyalgia. SSRIs appear to be useful adjuncts in the management of FMF patients who continue to have attacks despite regular colchicine treatment.