Streptococcus suis is an important swine pathogen responsible for economic losses to the swine industry worldwide. There is no effective commercial vaccine against S. suis. The use of autogenous (“bacterin”) vaccines to control S. suis outbreaks is a frequent preventive measure in the field, although scientific data on immunogenicity and reduction in mortality and morbidity are scarce. The goal of our study is to experimentally evaluate the immunogenicity and protective efficacy against homologous challenge in weaned piglets of a S. suis serotype 2 bacterin-based vaccine formulated with six different commercial adjuvants (Alhydrogel®, Emulsigen®-D, Quil-A®, Montanide™ ISA 206 VG, Montanide™ ISA 61 VG, and Montanide™ ISA 201 VG). The vaccine formulated with Montanide™ ISA 61 VG induced a significant increase in anti-S. suis antibodies, including both IgG1 and IgG2 subclasses, protected against mortality and significantly reduced morbidity and severity of clinical signs. Vaccines formulated with Montanide ISA 206 VG or Montanide ISA 201 VG also induced a significant increase in anti-S. suis antibodies and showed partial protection and reduction of clinical signs severity. Vaccines formulated with Alhydrogel®, Emulsigen®-D, or Quil-A® induced a low and IgG1-shifted antibody response and failed to protect vaccinated piglets against a homologous challenge. In conclusion, the type of adjuvant used in the vaccine formulation significantly influenced the immune response and efficacy of the vaccine against a homologous challenge.