Sjogren’s syndrome (SS) is a debilitating, sight-threatening, systemic autoimmune disease with no effective treatment available. SS is characterised by lacrimal gland lymphocytic infiltration and epithelial cell death, as well as by the presence of serum autoantibodies. Patients have severe dry eyes and are at high-risk of developing corneal perforation and blindness. To investigate the onset of SS in mouse models previous studies have reported that removal of the ovaries accelerated disease in susceptible mice, with lymphocytic infiltration preceding goblet cell apoptosis. In this paper cytokine levels in ovarectomised mice were studied. The results show that levels of proinflammtory cytokines interleukin-1β, tumour necrosis factor-α and IL-4 were elevated early after surgery which anti-inflammatory IL-10 was only raised at later time points. These changes were not seen in resistant mouse strains following ovarectomy. Likewise increased levels of anti-Ro/SSA were seen in susceptible strains only. Physiological doses of E2 or dihyrotestosterone (DHT) at time of OVX prevented the upregulation of cytokines and the presence of autoantibodies in these animals. These data show a strong link between ovarian hormones and onset of SS in mice of the appropriate genetic background. Genome-wide association studies have identified several genes to be linked to SS including some involved in the immune response. Coupled with the female predisposing to this condition this paper identifies novel pathways involved in the onset of SS that should be explored.