Abstract Objectives The objectives were to compare the personality of fibromyalgia (FM) patients with other chronic painful and nonpainful disorders considering the confusion due to psychopathology and to assess the clustering of FM patients according to their personality profile. Methods Differences in the NEO Five-Factor Inventory between FM, non-FM chronic pain and drug-resistant epileptic patients were assessed including the confounding effect of demographics and psychopathological status by multivariate regression analysis. Clustering of FM patients was assessed by two-step cluster analysis. Differences in clinical severity and psychosocial problems between subgroups and their outcome 6 months after multidisciplinary treatment were assessed. Results The final sample comprised 874 patients. Once the effect of confounding variables was considered, clinically nonsignificant differences in personality were observed between groups. FM patients could, however, be grouped into two clusters. Cluster 1 was characterized by higher neuroticism and lower extraversion and showed a worse pretreatment clinical state including more psychosocial problems. In spite of having reached a wider general improvement at 6-month follow-up, Cluster 1 patients remained more anxious and depressed. Conclusions Identifying personality-based subgroups of FM might allow implementing specific preventive strategies. FM treatment might be optimized by increasing medication compliance, improving therapeutic alliance and testing different therapeutic options and treatment sequencing for each personality subgroup.