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Objective:To delineate the comparative immunomodulatory roles of H1R-H4R in antibody generation profile in rabbit model. Methods:The cohort comprised of eight groups containing 18 (9 male and 9 female) rabbits in each group. Group I remained non-immunized and received only vehicle (sterile distilled water, 1 mL/kgíb.i.d.) intramuscularly. Group II received vehicle (1 mL/kg í b.i.d.) while Groups III-VII (drugs-treated) received subcutaneous histamine (100μg/kg í b.i.d.), and intramuscular H1R-antagonist (pheniramine, 10 mg/kg í b.i.d.), H2R-antagonist (ranitidine, 10 mg/kg í b.i.d.), H3R-antagonist (iodophenpropit, 1μg/kgíb.i.d.) and H4R-antagonist (JNJ 7777120, 10μg/kgíb.i.d.), and Group VIII DMSO (1 mL/kgíb.i.d.), respectively for 10 days (starting from day 1). They were subsequently immunized with intravenous injection of sheep red blood cells (SRBC) at day 3. The estimation of serum Igs, IgM and IgG were done by ELISA, and observed at day 0 (pre-immunization), and 7, 14, 21, 28 and 58 (post-immunization). Results: It was shown that histamine and HRs-antagonists could influence a detectable antibody response to SRBC as early as day 7-post-immunization (post-I), which lasted until day 58 post-I. The results were found statistically significant (P<0.05). Conclusions:This study suggests that histamine receptors play important roles in modulation of antibody generation in which H1R, H2R and H4R have immunosuppressive roles and conversely, H3R playes an immune enhancing role. The findings of this study may have clinical significance and provide the baseline information for future study.