The role of the immunogenicity evaluation of biosimilar candidates, in direct comparison with the reference product, is to provide assurance of absence of clinically relevant differences in undesirable immune responses to the different versions of a given biological medicinal product. Ideally, the manufacturing process would be locked prior to performing any comparative clinical studies, and the drug product formulation–primary container combination to be marketed would be used for the clinical immunogenicity evaluation. The most challenging practical aspect for the immunogenicity evaluation is the development and validation of assays to detect antidrug antibodies (ADAs) to the product versions being compared, since there are many potentially confounding factors for data interpretation. This chapter shares the experience gained in the evaluation of comparative immunogenicity of biosimilar and reference products to meet EU and US regulatory standards, suggests strategies for overcoming some of the challenges, and reflects on how unresolved issues might be addressed.