Measles virus (MV)-neutralizing antibodies in sera from vaccinated subjects are mainly directed against the haemagglutinin (H) protein. It has been shown previously that depletion of vaccination-induced H-specific antibodies by co-culture of sera with cells expressing the MV Edmonston strain H glycoprotein resulted in almost complete elimination of neutralizing activity. In the present study, MV H and/or fusion (F) protein-specific antibodies were depleted from sera of naturally immune subjects. Early convalescent samples were collected 1.5 years after a well-characterized measles outbreak in Luxembourg caused by a genotype C2 virus, whilst late convalescent samples were collected from healthy Dutch subjects born between 1960 and 1970. Depletion of both H- and F-specific antibodies completely eliminated virus-neutralizing (VN) activity against MV Edmonston. However, in the early convalescent samples, residual VN antibody against wild-type MV genotype C2 was detected. This demonstrated that, although the majority of MV-specific VN antibodies recognized epitopes conserved between different genotypes, genotype-specific VN epitopes were also induced. In sera depleted of H-specific antibodies only, VN activity against MV Edmonston was not completely eliminated, demonstrating the presence of F-specific VN antibodies. In conclusion, this study demonstrated that a fraction of VN antibodies induced by wild-type MV genotype C2 does not neutralize MV strain Edmonston. In addition, it was shown that, in sera from naturally immune donors, the majority of VN antibodies are specific for MV H protein, but up to 10% of neutralizing antibodies are specific for MV F protein.