Safety of live vaccines is questioned in children with inflammatory bowel diseases and after liver transplantation receiving immunosuppressive therapy. The objective was to monitor the immunogenicity and safety of attenuated live vaccines against measles, mumps and rubella (MMR) in children receiving immunosuppressive therapy. In this prospective multicenter observational study (DRKS00014569) 22 children and adolescents with incomplete MMR vaccination status were identified. Following individual assessment of vaccination readiness with stable immunosuppressive therapy in the last three months with no evidence of underlying disease activity, a risk-benefit assessment regarding vaccination with live-attenuated vaccines was performed. A checklist was used to assess the immune status based on thresholds for leukocyte, lymphocyte and CD4+ T cell counts, serum immunoglobulin G and M levels and detectable in vitro T cell activation. Sixteen patients were vaccinated against MMR, eleven after liver transplantation and five with inflammatory bowel disease. At the time of vaccination, four patients were receiving moderate (e.g., tacrolimus drug level below 5 ng/ml), eleven were receiving high-intensity immunosuppression (e.g. anti-tumor-necrosis factor agents, mycophenolate mofetil) and one child had previously discontinued immunosuppressive treatment. There were no serious adverse events or complications related to the vaccination. In children receiving immunosuppressive medications, the seroconversion rate for measles after the first MMR vaccination was 73.3 % (11/15) and after the second vaccination 80 % (12/15). Specific in vitro lymphocyte reactivity to measles antigen was detectable in three out of four patients after vaccination. This study shows that MMR vaccination can be carried out under immunosuppressive therapy in selected patients without relevant side effects, and a specific humoral and cellular immune response could be achieved.