Porphyromonas gingivalis, a keystone pathogen in periodontitis, secretes an array of virulence factors including gingipains via the type IX secretion system (T9SS). Inactivation of any component of the T9SS leads to the accumulation of secreted proteins in unprocessed and, in the case of progingipains, inactive forms in the periplasm. To cast light on the paradox that active gingipains are essential for P. gingivalis fitness in vivo but a functional T9SS is not (Frontiers in Cellular and Infection Microbiology, 2017, 7:378), we have compared virulence of wild-type P. gingivalis W83 and the gingipain-null strain with isogenic mutants deficient in individual T9SS components. Using an in vivo subcutaneous chamber mouse model of infection, gingipain-null strain secretion mutants showed no virulence, but their pathogenic potential was reconstituted by coinfection with a low number of the parental strain. Apparently the same mechanism compensated fitness of mutants lacking functional T9SS the transposon library. In contrast to the parental strain, all mutants elicited significantly lower but an effective inflammatory immune response, which cleared infection and prevented systemic dissemination of P. gingivalis to organs. There were no significant differences in immune responses to different secretion mutants, which were generally more stimulatory than the gingipain-null strain. Together, these results indicate that functional T9SS is essential for P. gingivalis virulence apparently through delivery of active gingipains to the bacterial surface. Therefore, T9SS is a legitimate target for drug development to treat periodontitis.