Background: Previous studies have shown that many personality traits are associated with fibromyalgia (FM), worsening both the quality of life and psychological distress of patients. Despite the high comorbidity of psychopathological disorders in this syndrome and their association with immature defense styles, few studies have examined the defense mechanisms used by FM patients. The main aim of our study was to investigate personality traits and defense mechanisms in FM patients compared to in a healthy control group (HC). Moreover, we investigated the effect of personality traits and defense mechanisms on psychological distress in both FM and HC groups. Methods: A total of 54 women with FM and 54 healthy women completed the (1) Temperament and Character Inventory—Revised; (2) the Toronto Alexithymia Scale; (3) the Defense Style Questionnaire; and (4) the Hospital Anxiety and Depression Scale. Results: The results indicated that FM patients display higher alexithymia, higher harm avoidance, lower self-directedness, lower persistence, and the higher use of a maladaptive defense style compared to HC. We found that alexithymia, harm avoidance, and maladaptive defense style are significant predictors of patients’ psychological distress. Moreover, harm avoidance and adaptive defense style significantly predicted psychological distress in the HC group. Conclusion: The present study is the first to explore the contribution of both defense mechanisms and personality characteristics on the psychological distress of FM patients. Our findings have important clinical implications and may help diagnose and treat FM patients more in depth.