Background: Salivary gland dysfunction is one of the key manifestations of Sjogren's syndrome. Objectives: (1) To assess prospectively loss of function of individual salivary glands in patients with primary and secondary Sjogren's syndrome in relation to disease duration and use of immunomodulatory drugs. (2) To study changes in sialochemical and laboratory values and subjective complaints over time. Methods: 60 patients with Sjogren's syndrome were included in this study. Whole and gland-specific saliva (parotid and submandibular/sublingual (SM/SL)), samples were collected at baseline and after a mean of 3.6 (SD 2.3) years of follow-up. Disease duration was recorded for all patients. Results: Patients with Sjogren's syndrome with short disease duration had significantly higher stimulated flow rates at baseline than those with longer disease duration (p < 0.05). When compared with healthy controls, the decrease in SM/SL flow rates at baseline was more prominent than that in parotid flow rates (p < 0.05). Over time, there was a significant further decrease of stimulated flow rates, especially of the parotid gland, accompanied by increasing problems with swallowing dry food (p < 0.05). The decrease was independent of the use of corticosteroids or disease-modifying antirheumatic drugs (DMARDs). Sialochemical variables remained stable. Conclusions: Early Sjogren's syndrome is characterised by a decreased salivary gland function (parotis > SM/SL), which shows a further decrease over time, regardless of the use of DMARDs or steroids. Patients with Sjogren's syndrome with longer disease duration are characterised by severely reduced secretions of both the parotid and SM/SL glands. These observations are relevant for identifying patients who would most likely benefit from intervention treatment.