Objective To determine the influence of the use of tibolone on the frequency of flares of systemic lupus erythematosus (SLE) in postmenopausal patients. Methods Thirty patients with inactive or controlled SLE were included in the study. Patients were randomized to receive a 12-month course of either tibolona (2.5 mg/day) or placebo. The following were investigated: hypoestrogenism symptoms by Kupperman index, weight; anti-dsDNA antibodies; SLE flares (frequency) assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI); and biochemical profile (total cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides, complement components [C3/C4], α1-acid glycoprotein, urea, creatinine, 24-h proteinuria, C-reactive protein and erythrocyte sedimentation rate). Results The reduction in Kupperman index was greater in the patients using tibolone than in those using placebo. The mean SLEDAI was not different between the groups during the study as well as SLE flare frequency (tibolone: 2/15 [13.3%] vs. placebo: 1/15 [6.7%]; p = 0.54). All cases of flares were considered mild to moderate. Although the groups were similar at the baseline evaluation, after 6 and 12 months of treatment lower values were found in the tibolone group for triglycerides (6 months: 161.6 ± 30.9 mg/dl vs. 194.4 ± 46.5; p = 0.04; 12 months 163.7 ± 29.8 mg/dl vs. 204.1 ± 49.9 mg/dl; p = 0.02; tibolone vs. placebo group, respectively) and for HDL-C (6 months: 40.7 ± 10.7 mg/dl vs. 53.4 ± 16.5; p = 0.02; 12 months: 47.2 ± 7.9 mg/dl vs. 63.2 ± 16.3 mg/dl; p < 0.01; tibolone vs. placebo group, respectively). There were no differences between the two groups in any of the remaining variables. Conclusion In patients with inactive or stable SLE, the short-term use of tibolone did not significantly affect the frequency of flares. In addition, tibolone was well tolerated and effective to control hypoestrogenism related symptoms in SLE patients.