Gonadal sex hormones may account for the sexual dimorphism in the immune response and for the greater incidence of autoimmune disease in females. We have previously reported the presence of progesterone (P) deficiency in female patients with thyroid and ovarian autoimmune disease. In this context, the hormonal profile in 9 women with rheumatoid arthritis (RA) and in 9 age-matched ealthy women, were evaluated to verify the presence of a steroid hormone secretion impairment in a systemic autoimmune disease, further supporting our hypothesis of P deficiency involvement. P and androgen plasma levels, in the luteal phase, were significantly lower (p < 0.05 and 0.005, respectively) in RA patients than in the control group, with a consequent decrease of the free androgen index. Moreover, despite normal cortisol values, corticosterone (B) plasma levels were significantly higher in the RA patients (p < 0.01 and 0.05 in follicular and luteal phase, respectively). Therefore, our present data confirm the androgen deficiency in patients with a systemic autoimmune disease, such as RA and support the immunomodulator effect of P. Finally, the higher B plasma levels in RA patients may suggest the presence of a slight impairment of the immune hypothalamic-pituitary-adrenal axis (HPAA), supporting its role in certain phases of RA pathogenesis. In conclusion, in addition to androgens, the immunomodulator role of P should also be taken into account in the pathogenesis of the systemic autoimmune disease.