Abstract Background and Aims Prednisolone monotherapy is the most used initial immunosuppressive treatment for nephrotic syndrome in adults with Minimal Change Disease (MCD) but choice of treatment in relapsing MCD is not as well described. With the introduction of new drugs and increased concern relating to the adverse events of prednisolone, treatment might have changed over time. The aim of this study is to describe changes in daily clinical practice of relapsing MCD within the last 35 years. Method A multicenter, retrospective analysis of adult patients with biopsy proven MCD from 13 hospitals from 1987-2022 in Denmark and the Netherlands. Patients were identified from the pathology registers. Information on treatment and clinical outcomes was retrieved from health records. Relapse is defined when the nephrologist found indication to restart an immunosuppressive treatment or increase the ongoing immunosuppression in patients in partial or complete remission. Results We included 167 Dutch and 72 Danish patients (n = 239) with MCD. Most patients (n = 205, 86%) were initially treated with prednisolone monotherapy. Overall, 93% (n = 220) gained remission and 56% (n = 123) of those who went into remission had one or more relapse with 68% of these occurring in the first year after remission. At the time of relapse, 89% were in complete remission and 11% were in partial remission. At first relapse, prednisolone monotherapy was the most prescribed treatment both before and after 2010 (69% and 45%, respectively), while the use of CNI tripled after 2010 (p = 0.002) (10% to 32%). At second relapse, prescription of CNI after 2010 showed a five-fold increase compared with before 2010 (49% vs 10%, respectively) while the use of prednisolone monotherapy was halved (50% to 24%). The use of cyclophosphamide decreased by two-thirds (32% to 10%) after 2010. Before 2010, 54% of patients received prednisolone monotherapy for their third to 14th relapse, but after 2010 this decreased to 26%. The use of rituximab and CNI both increased and after 2010 these were both prescribed to about one third of patients at third to 14th relapse. The use of cyclophosphamide decreased from 30% to 2% comparing before and after 2010. Rituximab was only used after 2010, and more frequently with the number of relapses (6% at first relapse and 36% at third to 14th relapse). Regardless of the choice of treatment the rates of remission were high. Conclusion The treatment of relapses has changed over time with a reduced use of prednisolone monotherapy and cyclophosphamide and increased use of CNI and rituximab.