Abstract Background and Aims The regional epidemiology of Systemic lupus erythematosus (SLE) and lupus nephritis (LN) within the same country is poorly understood. Being a rare disease, its severity may be influenced by local expertise and treatment protocols, especially when healthcare systems are fragmented, like in Spain (17 different healthcare systems in 17 Autonomous Community (AACC), population range 319.796 to 8.472.407), resulting in potentially different levels of expertise in regional referral centers. Additional heterogeneity may derive from different specialists (rheumatology, internal medicine, nephrology) caring for SLE and LN. We aim to investigate the disease burden of SLE and LN in Spain and its AACC between 2019 and 2021, and to characterize factors that may influence this burden. Method The primary diagnostic data and average cost of SLE and NL hospitalization were extracted from the Minimum Basic Data Set (MBDS, Ministry of Health) that contains data from private and public hospitals. Sociodemographic data were obtained from the National Statistics Institute. Results From 2019 to 2021, there were 872 LN and 3612 SLE nationwide hospitalizations. Over 60% occurred in Andalucia, Catalonia, and Madrid, which account for 48% of Spanish population. Nationwide, the incidence of LN and SLE hospitalization was 1.44 and 4.59 per 100 000, respectively. However, regional variability was large, with a 3.7-fold difference for LN and a 7.3-fold difference for SLE between Madrid and Valencia, 2 of the more populated AACC. The median LN/SLE hospitalization ratio was 0.33. Relative risk for hospitalization, compared to the national mean, ranged in AACC from 0.37 (Baleares) to 2.55 (La Rioja) for LN and from 0.22 (Baleares) to 3.67 (Ceuta and Melilla) for SLE (Fig. 1A). Heterogeneity was larger at the provincial level where 10/50 provinces had significantly higher or lower relative risk than the national mean (Fig. 1B). The length of SLE/LN hospitalizations was very variable across specialties and AACC. There was a trend for shorter duration in Nephrology and longer in Internal Medicine for both LN and SLE. Nephrology was mainly responsible (76%) for LN hospitalization, with regional differences. For SLE hospitalization, Nephrology was also most commonly in charge. Heterogeneity was larger at the province level within the same AACC. The average All-Patient-Related (APR) cost per LN and SLE hospitalization episodes was €5254 and €4376, respectively, with significant geographical variability. Total annual hospitalization costs varied significantly among AACC, ranging from €8683 (Ceuta and Melilla) to €682512 (Catalonia) for LN and from €68361 (Ceuta and Melilla) to €2229456 (Madrid) for SLE. Adjusted per million population, total LN hospitalization cost ranged from €27920 (Baleares) to €179248 (La Rioja), and SLE cost from €91563 (Baleares) to €399693 (Ceuta and Melilla). When adjusted by €1000 of average household net income, the budget burden of LN hospitalization was highest in La Rioja (€5812 per €1000 of average household net income) and lowest in Baleares (€809 per €1000), while for SLE was highest in Murcia (€11186 per €1000) and lowest in Baleares (€2652 per €1000) (Fig. 2A,B). Conclusion In conclusion, the burden of LN and SLE hospitalization is heterogeneous across and within Spanish AACC, with large regional differences in the distribution of cases, costs and specialists who care for these patients. The analysis of these differences may contribute to benchmarking of best practices, decreasing clinical practice heterogeneity, optimizing care for SLE and LN and improving outcomes.