Objective: Stress can play an important role in etiology of fibromyalgia syndrome (FMS) by activating the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic nervous system (SNS), and altering the immune system. The current study examined the influence of catechol-O-methyltransferase (COMT) Val158Met genotypes on salivary markers of HPA axis (cortisol), SNS (alpha-amylase), and immune (IgA) systems in women with FMS. Methods: Seventy-six women with FMS diagnosed according to the American College of Rheumatology criteria participated in the study. Salivary cortisol, alpha-amylase activity, salivary flow rate, and IgA concentration were collected from nonstimulated saliva. A numerical pain rate scale (0 to 10) was used to assess the intensity of pain, whereas functional ability was determined using the Fibromyalgia Impact Questionnaire (FIQ). After amplifying Val158Met polymorphisms by polymerase chain reaction, 3 COMT genotypes were considered: Val/Val, Val/Met, and Met/Met. Results: Women with FMS with the Met/Met genotype reported higher alpha-amylase activity, lower salivary flow rate, and lower IgA concentration than those women with FMS carrying the Val/Met (P < 0.05) or Val/Val (P < 0.01) genotypes. No difference in cortisol concentration (P > 0.70) was found. These results were not associated with the intensity of pain, disability, and medication intake. Conclusions: The results suggest that women with FMS with the Met/Met genotype exhibit greater disturbed activity of the SNS and humoral immune system. These results provide initial evidence of a link between Val158Met polymorphism and dysfunctions in the SNS and humoral immune system in women with FMS.