Virulent Aeromonas hydrophila (vAh) attributes nearly $35 million dollars in economic losses within the southeastern catfish aquaculture industry. This bacterial pathogen infects channel and hybrid catfish inducing skin necrosis, internal and external hemorrhaging, and exophthalmia. Farmers can lose over 50% of a harvest yield in less than a week when infected, increasing the urgency for more effective preventative measures. Bacterin vaccines typically mediate a high antibody response and even more so when boosted. Recently, our research team formulated and tested an oral bacterin vaccine against various vAh strains with and without the inclusion of an adjuvant. Bacterin vaccines were made for S14-452 (1.10 x107) and ALG-15-097 (1.0 x107). At 3 and 12 weeks, bacterin vaccines showed protection against both vAh strains and demonstrated cross-protection. Antibody presence was proposed as a potential mechanism of protection; thus the aim of the study was to assess whether passive immunization with anti-vAh whole serum provides protection upon vAh challenge. To evaluate protection, antiserum was generated from 2 vAh strains (S14-452 and ML09-119) and used to passively immunize channel catfish with the following treatment groups: control sera, heat-inactivated control sera, vAh sera, and heat-inactivated vAh sera. Three trials were conducted. For trials 1 and 2, fish were injected with 100mL of heat and non-heat-inactivated antisera (T1: ML09-119; T2: S14-452) and were exposed with the corresponding vAh strain 24 h post-injection (1.4 × 10⁷ CFU mL⁻¹; ML09-119 and 1.2 × 10⁷ CFU mL⁻¹; S14-452). The final trial evaluated cross-protection potential with the following groups: heat-inactivated S14-452, ML09-119, & control sera, and non-heat-inactivated S14-452, ML09-119, & control sera and where exposed to ALG-15-097 (1.1 × 10⁷ CFU mL⁻¹). In all three trials, 100% protection was observed in all groups injected with vAh heat and non-heat-inactivated sera. Fish passively immunized with heat and non-heat-inactivated control serum exhibited 30-50 % survival dependent on the trial. This level of efficacy demonstrates the importance of antibodies in potentially mediating protection and cross-protection against various vAh strains. A Western blot analysis was conducted to determine whether antisera generated against one isolate of vAh cross-reacted with antigens of other vAh isolates and a typical A. hydrophila strain. Antiserum generated exhibited antibodies that cross-reacted with proteins and the LPS of the homologous and heterologous isolates, even the typical A. hydrophila isolate. Our findings point to mechanisms of immunity against vAh and guide vaccine development, ultimately preventing large-scale mortalities caused by vAh.