Developing countries are burdened withShigelladiarrhea. Understanding mucosal immune responses associated with naturalShigellainfection is important to identify potential correlates of protection and, as such, to design effective vaccines. We performed a comparative analysis of circulating mucosal plasmablasts producing specific antibodies against highly conserved invasive plasmid antigens (IpaC, IpaD20, and IpaD120) and two recently identified surface protein antigens,pan-Shigellasurfaceprotein antigen 1 (PSSP1) and PSSP2, common to all virulentShigellastrains. We examined blood and stool specimens from 37 diarrheal patients admitted to the Infectious Diseases & Beliaghata General Hospital, Kolkata, India. The etiological agent of diarrhea was investigated in stool specimens by microbiological methods and real-time PCR. Gut-homing (α4β7+) antibody-secreting cells (ASCs) were isolated from patient blood by means of combined magnetic cell sorting and two-color enzyme-linked immunosorbent spot (ELISPOT) assay. Overall, 57% (21 of 37) and 65% (24 of 37) of the patients were positive forShigellainfection by microbiological and real-time PCR assays, respectively. The frequency of α4β7+IgG ASC responders against Ipas was higher than that observed against PSSP1 or PSSP2, regardless of theShigellaserotype isolated from these patients. Thus, α4β7+ASC responses to Ipas may be considered an indirect marker ofShigellainfection. The apparent weakness of ASC responses to PSSP1 is consistent with the lack of cross-protection induced by naturalShigellainfection. The finding that ASC responses to IpaD develop in patients with recent-onset shigellosis indicates that such responses may not be protective or may wane too rapidly and/or be of insufficient magnitude.