H7 avian influenza viruses represent a major public health concern, and worldwide outbreaks raise the risk of a potential pandemic. Understanding the memory B cell response to avian (H7) influenza virus infection in humans could provide insights in the potential key to human infection risks. We investigated an epizootic of the highly pathogenic A(H7N7) in the Netherlands, which in 2003 led to infection of 89 persons and one fatal case. Subtype-specificity of antibodies were determined for confirmed H7N7 infected individuals (cases) (n = 19), contacts of these cases (n = 21) and a comparison group controls (n = 16), by microarray, using recombinant hemagglutinin (HA)1 proteins. The frequency and specificity of memory B cells was determined by detecting subtype-specific antibodies in the culture supernatants from in vitro stimulated oligoclonal B cell cultures, from peripheral blood of cases and controls. All cases (100%) had high antibody titers specific for A(H7N7)2003 (GMT > 100), whereas H7-HA1 antigen binding was detected in 29% of contacts and 31% of controls, suggesting that some of the H7 reactivity stems from cross reactive antibodies. To unravel homotypic and heterotypic responses, the frequency and specificity of memory B cells were determined in 2 cases. Ten of 123 HA1 reactive clones isolated from the cases bound to only H7- HA1, whereas 5 bound both H7 and other HA1 antigens. We recovered at least four different epitopal reactivities, though none of the H7 reactive antibodies were able to neutralize H7 infections in vitro. Our study serologically confirms the infection with H7 avian influenza viruses, and shows that H7 infection triggers a mixture of strain -specific and cross-reactive antibodies.