From May 2016 to March 2017, 22 poultry outbreaks of avian influenza A(H5N1) were reported in Cameroon, mainly in poultry farms and live bird markets. No human cases were reported. In this study, we sought to describe the 2016 A(H5N1) outbreak strain and to investigate the risk of infection in exposed individuals. We find that highly pathogenic influenza subtype A(H5N1), clade 2.3.2.1c from Cameroon is closely related phylogenetically and antigenically to strains isolated in central and western Africa at the time. No molecular markers of increased human transmissibility were noted; however, seroconversion was detected in two poultry workers (1.5% of total screened). Therefore, the continued outbreaks of avian influenza in poultry and the risk of zoonotic human infection highlight the crucial need for continued and vigilant influenza surveillance and research in Africa, especially in areas of high poultry trade, such as Cameroon.