An important goal in the management of systemic lupus erythematosus (SLE) is the prediction of relapses. This study assesses whether anti-nucleosome antibodies (anti-NCS) increase the risk of renal relapse in inactive SLE. A prospective cohort of 115 patients with inactive SLE (M-SLEDAI ≤ 2) were followed for 12 months to assess the development of relapse (increase of M-SLEDAI ≥ 4) and specific renal flare (renal SLEDAI ≥ 4). At baseline, we identified potential risk factors for relapse, including anti-NCS. At baseline, 18 (16%) of the 115 patients with inactive SLE were anti-NCS positive. At the 12-month follow-up, anti-NCS-positive patients had a higher incidence of renal relapse compared to anti-NCS-negative patients (38.9% vs 13.4%, respectively). In Cox regression analysis, after adjusting for age, disease duration, anti-dsDNA, and immunosuppressive drugs, the presence of anti-NCS positivity at baseline increased the risk of renal relapse (HR: 5.31, 95% CI 2.03-13.92). Nevertheless, there were no differences in the incidence of other relapses in anti-NCS-positive versus anti-NCS-negative. Our results indicate that in inactive SLE, anti-NCS determination can be useful for identifying patients with a higher risk of developing renal relapse. Interestingly, this study identified that continued use of oral immunosuppressive therapy in patients with inactive SLE can reduce the risk of renal relapse.