OBJECTIVES: The differences in the active substance of biosimilars compared to their originator reference product can cause risks that are unique to biologics, mainly: immunogenicity, long-term safety risks, and lack of efficacy. These risks are unknown at the launch of a biosimilar and can lead to unexpected costs for payers. The aim of this abstract is to describe a methodology for evaluating the unknown risks of biosimilars. METHODS: A structured literature review revealed that for many biologics, post-marketing observational studies have been set up to identify long-term safety and efficacy outcomes. These studies are a useful source of information to quantify the unknown risks of biosimilars and define methods of minimizing those risks. The information required is product- and population-specific. This information first includes potential safety issues such as immunogenicity (all biologics), serious infections and autoimmune disorders (anti-TNFs, interferons), and increased mortality and cardiovascular events (epoetin). Second, information is available on long-term benefits such as clinical outcomes that improve overall survival (e.g. reduced recurrence of malignancies through interferon use and reduced cardiovascular events through insulin use), reduction in healthcare resource utilization (epoetin, somatropin), and proportion of long-term responders (figrastim, anti-TNF, somatropin). Finally, observational data can be used to optimize treatment regimens to achieve maximum treatment benefit (epoetin, insulin, somatropin). All these data can be used in an economic evaluation where the unknown risks for biosimilars are quantified through worst- and best-case scenarios. CONCLUSIONS: Often, payers are attracted to biosimilars that have the lowest acquisition costs.  However, the risks of unknown information for these biosimilars should be valued against the lower price of these drugs. Observational data for the originator biologic product can be leveraged to quantify these risks. This can help determine for which drugs and for which populations the unknown risks outweigh the reduction in acquisition costs.