To further establish potential differences according to sex in systemic lupus erythematosus (SLE) patients from Southern Europe. We assessed clinical and epidemiological data of patients diagnosed with SLE according to the 1982 American College of Rheumatology classification criteria at the single hospital for a well-defined population of Northwest Spain, between 1987 and 2006. Prevalence in December 2006 and age-standardized incidence rates in the whole period were estimated. Kaplan-Meier method was used in order to estimate the probability of survivorship. Women outnumbered men [127 (84.7%) vs. 23 (15.3%)]. The median age at the time of disease diagnosis in men was 54 years versus 43 in women (p < 0.001). Annual incidence rates were higher in women [5.9 (95% confidence interval--CI 4.9-7.0) per 100,000 population] than in men [1.1 (95% CI 0.7-1.7) per 100,000 population; p < 0.001]. Raynaud's phenomenon was more common in women (40.9 vs. 3.0%; p = 0.01). While the frequency of secondary Sjögren's syndrome was increased in women (p = 0.02), renal disease at the time of diagnosis (39.1 vs. 15.0%; p < 0.01) and over the course of the disease was more common in men (43.5 vs. 24.4%; p = 0.06). Higher frequency of thrombocytopenia (39.1 vs. 16.5%; p = 0.01) and lower frequency of anti-SSA (13.0 vs. 31.5%; p = 0.08) and anti-SSB (0 vs. 17.7%; p = 0.03) were observed in men. The 5- and 10-year survival probabilities were nonsignificantly reduced in men (91.3 and 78.3 3% vs. 94.6 and 89.2% in women). The frequency of some clinical manifestations is different in men and women with SLE. Higher awareness of these peculiarities may help to establish appropriate diagnosis and management of SLE in men.