The pathogen of Lyme disease, Borrelia burgdorferi, produces a putative surface protein termed "surface-located membrane protein 1" (Lmp1). Lmp1 has been shown previously to assist the microbe in evasion of host-acquired immune defenses and in the establishment of persistent infection of mammals. Here, we show that Lmp1 is an integral membrane protein with surface-exposed N-terminal, middle, and C-terminal regions. During murine infection, antibodies recognizing these three protein regions were produced. Separate immunization of mice with each of the discrete regions exerted differential effects on spirochete survival during infection. Notably, antibodies against the C-terminal region primarily interfered with B. burgdorferi persistence in the joints, while antibodies specific to the N-terminal region predominantly affected pathogen levels in the heart, including the development of carditis. Genetic reconstitution of lmp1 deletion mutants with the lmp1 N-terminal region significantly enhanced its ability to resist the bactericidal effects of immune sera and also was observed to increase pathogen survival in vivo. Taken together, the combined data suggest that the N-terminal region of Lmp1 plays a distinct role in spirochete survival and other parts of the protein are related to specific functions corresponding to pathogen persistence and tropism during infection that is displayed in an organ-specific manner. The findings reported here underscore the fact that surface-exposed regions of Lmp1 could potentially serve as vaccine targets or antigenic regions that could alter the course of natural Lyme disease.