In 1976, the emergence of a new swine-origin influenza virus prompted concerns about an impending influenza pandemic. Although the outbreak never materialized, the epidemiological link between Guillain-Barre syndrome, a potentially severe peripheral nerve disorder, and the influenza vaccines developed against this virus caught public health officials, clinicians, and the public by surprise. Subsequently, a great deal of scrutiny has been placed on the possible risk of other formulations of influenza vaccine causing this adverse event. Several epidemiologic and biological assessments have been performed in subsequent years to assess this risk, yet considerable uncertainty remains among health care providers about the possible association. The development and rapid implementation of vaccines against the pandemic 2009 A(H1N1) influenza virus once again highlighted this issue. This article reviews the evidence for and against the association of the 1976 influenza vaccines and subsequent seasonal influenza vaccines with the development of Guillain-Barré syndrome.