ABSTRACT Aims Hemophore-like proteins sequester heme from host hemoproteins. We aimed to determine whether the host immune system can recognize not only Porphyromonas gingivalis HmuY but also its homologs expressed by other periodontopathogens, and how periodontitis influences the production of respective antibodies. Methods The reactivity of total bacterial antigens and purified proteins with serum IgG antibodies of 18 individuals with periodontitis and 17 individuals without periodontitis was examined by enzyme-linked immunosorbent assay (ELISA). To compare IgG reactivity between groups with and without periodontitis and within the various dilutions of sera, statistical analysis was performed using the Mann-Whitney U-test and two-way ANOVA test with the post-hoc Bonferroni test. Results Individuals with periodontitis produced IgG antibodies reacting more strongly not only with total P. gingivalis antigens (P = 0.0002; 1:400) and P. gingivalis HmuY (P = 0.0016; 1:100) but also with Prevotella intermedia PinA (P = 0.0059; 1:100), and with low efficiency with P. intermedia PinO (P = 0.0021; 1:100). No increase in the reactivity of IgG antibodies with Tannerella forsythia Tfo and P. gingivalis HusA was found in individuals with periodontitis. Conclusions Although hemophore-like proteins are structurally related, they are differentially recognized by the host immune system. Our findings point to specific antigens, mainly P. gingivalis HmuY and P. intermedia PinA, whose immunoreactivity could be further investigated to develop markers of periodontitis.