The aim of the present study was to investigate the health-related quality of life (HRQOL) and mood conditions in familial Mediterranean fever (FMF) patients. Ninety FMF patients (F/M 60/30, median age 29) and 67 control subjects (F/M 46/21, median age 30) were included in this study. HRQOL was assessed with short form-36 (SF-36) and mood conditions were assessed with hospital anxiety depression scale (HADS). FMF patients had significantly lower mean scores on SF-36 physical components compared to the control group. However, mental components were comparable between groups. FMF patients were significantly more likely to have depression and anxiety compared to the control group [30 (33%) vs. 8 (12%), respectively, chi (2) = 9.58, OR (95% CI) = 3.7 (1.5-8.7), p < 0.01 for depression and 48 (53%) and 11 (16%), respectively, chi (2) = 22.31, OR (95% CI) = 5.8 (2.7-12.5), p < 0.001 for anxiety]. When frequency of anxious subjects was adjusted for the presence of concomitant depressive status as a confounding factor, the difference between the groups remained statistically significant [chi (2) = 11.86, OR (95% CI) = 5.4 (2.1-13.7), p < 0.01]. However, the difference of depression status between groups was not statistically significant when adjusted for the presence of concomitant anxiety status [chi (2) = 0.08, OR (95% CI) = 1.3 (0.5-3.8), p = 0.78] and FMF was found to be independently associated with only anxiety [OR (95% CI) = 7.1 (2.3-20.3)]. In addition, pure anxious FMF subgroup had significantly lower scores of mental health and mental component summary when compared to normal mood subgroup. In conclusion, FMF might adversely affect HRQOL. Depression and anxiety are more frequent in FMF patients than healthy subjects.