OBJECTIVES: The study’s objective was to assess the role of safety aspects in the overall AMNOG benefit assessment in Germany. Special attention was given to two aspects: (1) Are adverse events (AE) used systematically to change the benefit assessment in any direction? (2) Are safety aspects considered in the assessment in accordance with the scientific CHMP opinion? METHODS: 26 benefit assessments decided and published by the Federal Joint Committee (G-BA) between Jan 1st 2011 and Jun 6th 2013 were analyzed regarding the extent of harm. For each drug the extent of harm included with the consecutive influence on the overall benefit rating including potential changes in the overall rating scores was determined. Additionally, the safety aspects considered in the G-BA decision were compared to the CHMP assessments. RESULTS: For 19 of 26 drugs (73.1%), a greater or less harm vs. the comparator determined by the G-BA was considered. In 12 of these 19 substances (63.2%) the rating of the additional benefit drawn from efficacy results remained unaltered due to safety aspects. In 5 procedures (26.3%) the G-BA rated the additional benefit solely on the basis of less harm vs. the comparator. In 2 procedures (10.5%) the G-BA found a greater harm vs. the comparator which negatively impacted the overall rating. Statistically significant results of ‘overall incidence of AE’, ‘AE grade 3-4’, ‘serious AE’ and ‘AE leading to study withdrawal’ were always considered by the G-BA. In 8 cases (42.0%), the G-BA weighted safety aspects differently from the EMA in its overall rating process. CONCLUSIONS: The AE profile is of major importance in the AMNOG process. It changed in more than one third of the drug assessments (7 cases; 36.8%) the efficacy based benefit ratings. In 8 cases (42.0%) the G-BA assessment deviated from the conclusions considered by the EMA.