Objective The objective of this paper is to evaluate hospital admissions in systemic lupus erythematosus (SLE) patients through a retrospective population-based study analyzing hospitalization data during 2001–2012 in Sardinia, an Italian region with universal health system coverage. Methods Data on the hospital discharge records with the ICD-9-CM code for SLE (710.0) were obtained from the Department of Health and Hygiene and analyzed, mostly focusing on primary and non-primary diagnosis and Diagnosis-Related Group (DRG) code. In order to establish the significance of the annual trend for number and type of primary and non-primary discharge diagnosis, the two-tailed Cochran-Armitage test for trend was applied. In order to estimate SLE prevalence, data from administrative database and medical records were assembled. Results This study included 6222 hospitalizations in 1675 patients (87% women). Hospitalizations with SLE as primary diagnosis were 3782 (58.0%) and significantly decreased during the study period. The annual number of renal, hematologic and neuropsychiatric disorders as non-primary diagnosis associated with SLE remained constant; however, their percentage increased ( p < 0.0001) because of a declining number of admissions for SLE without associated diagnosis and without complications. Hospitalizations with SLE as non-primary diagnosis showed a significant upward trend in number and percentage of cerebrovascular accident ( p = 0.0004), acute coronary syndrome ( p = 0.0004) and chronic renal failure ( p = 0.0003) as underlying primary diagnosis, while complications of pregnancy, labor and childbirth ( p = 0.3375), malignancies ( p = 0.6608) and adverse drug reactions ( p = 0.2456) did not show statistically significant changes. Infections showed an increasing trend between 2001 and 2012 but did not reach statistical significance ( p = 0.0304). After correction for hospitalization (93.8%) and survival (91.1%) rates calculated over the study period, the 2012 SLE prevalence in Sardinia was estimated to be 99.3 per 100,000 inhabitants. Conclusions While overall hospitalizations for SLE patients declined, those for cerebrovascular accident, acute coronary syndrome and chronic renal failure as underlying primary diagnosis increased during the study period.