Enterotoxigenic E. coli (ETEC) causes hundreds of millions of cases of acute diarrheal illness in low- and middle-income regions, disproportionately in young children. To date, there is no licensed, broadly protective vaccine against these common but antigenically heterogeneous pathogens. One of the more highly conserved antigens of ETEC, EtpA, is an extracellular glycoprotein adhesin that preferentially binds to A blood group glycans on intestinal epithelia. EtpA contributes to increased severity of illness in A blood group individuals, elicits robust serologic and fecal antibody responses following infection, and has been associated with protection against subsequent infection. However, its utility as a protective antigen needs further examination. In the present studies, we examined whether parenteral vaccination with recombinant EtpA (rEtpA) could afford protection against intestinal colonization in a murine model of ETEC infection. Here, we demonstrate that intramuscular vaccination with rEtpA, adjuvanted with double mutant LT (dmLT), primes IgG predominant mucosal antibody responses to ETEC challenge. Notably, however, both antibody levels and avidity, as well as protection, were dependent on the vaccination schedule. Likewise, through electron microscopy polyclonal epitope mapping (EMPEM), we observed a different repertoire of epitopes targeted by antibodies after a more protracted vaccination schedule. Next, we explored the utility of IM immunization with alum-adjuvanted rEtpA. This elicited strong serologic and fecal IgG responses. Although accompanied by negligible IgA mucosal responses, EtpA alum-adjuvanted IM vaccination nevertheless protected against ETEC intestinal colonization. Collectively, these data suggest that EtpA could expand the portfolio of antigens targeted in ETEC subunit vaccine development.