Smoking affects several disease processes. Epidemiological studies have previously found a negative association between primary Sjogrens syndrome (pSS) and smoking. The aim of this study was to examine whether markers of disease activity and cytokine expression in pSS patients differ between ever and never smokers. Fifty-one consecutive pSS patients and 33 population controls were included in the study. Clinical and standard laboratory parameters were registered. Serum cytokines (IL-1 beta, IL-2, IL-3, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, IL-18, IL-33, IFN-alpha, IFN-gamma, TNF-alpha, EGF, BAFF, Fas-ligand, RANTES, TGF-beta 1) were assessed. A positive lip biopsy was less prevalent among ever smoking patients compared to never smokers (81 vs 100%; p = 0.03). However, except for TNF-alpha, which was higher in ever smokers, no differences in cytokine levels were found when comparing ever and never smoking pSS patients. Furthermore, no significant differences were found between ever and never smoking patients in the ESSDAI total score, IgG levels, or complement levels. However, IL-6, IL-12, IL-17 and IL-18 were significantly increased in pSS patients compared to controls. In this study, a negative association between ever smoking and positive lip biopsy was found, confirming previous reports. Expected differences in cytokine levels compared to controls were noted, but no major differences were found between ever and never smoking pSS patients. Taking into account the negative association between pSS diagnosis and smoking in epidemiological studies, possible explanations include a local effect of smoking on salivary glands rather than systemic effects by cigarette smoke.