Vaccination is one of the most important tools to protect pigs against infection with porcine reproductive and respiratory syndrome virus 1 (PRRSV-1). Although neutralizing antibodies are considered to represent an important mechanism of protective immunity, anti-PRRSV antibodies, in particular at subneutralizing concentrations, have also been reported to exacerbate PRRSV infection, probably through FcγR-mediated uptake of antibody-opsonized PRRSV, resulting in enhanced infection of, and replication in, target cells. Therefore, we investigated this pathway using sera from an animal experiment in which vaccine-mediated enhancement of clinical symptoms was observed. Three groups of six pigs were vaccinated with an inactivated PRRSV vaccine based on the PRRSV-1 subtype 3 strain Lena and challenged after a single or a prime-boost immunization protocol, or injected with PBS. We specifically tested if sera obtained from these animals can enhance macrophage infections, viral shedding, or cytokine release at different dilutions. Neither the presence of neutralizing antibodies nor general anti-PRRSV antibodies, mediated an enhanced infection, increased viral release or cytokine production by macrophages. Taken together, our data indicate that the exacerbated disease was not caused by antibodies.