Albino strains of Biomphalaria glabrata that are compatible with Schistosoma mansoni are commonly used to investigate snail-schistosome interactions, but whether they are all equally compatible is not known. In this study, compatibility with the Naval Medical Research Institute (NMRI) strain of S. mansoni was compared among 3 widely used albino strains: NMRI (the normal laboratory host for NMRI S. mansoni), M line, and University of Massachusetts Lowell (UML). Compatibility was assessed on the basis of infection prevalence following exposure to miracidia, the histological fate of sporocysts, and mitotic response in the snail amebocyte-producing organ (APO), a component of the internal defense system (IDS). Infection prevalence in UML was nearly identical to that in NMRI but was significantly lower in M line. Although the APO of UML showed no response to infection over the course of 9 days, mitotic activity was elevated in the APO of NMRI and M line, with that in M line being higher and more prolonged than in the APO of resistant BS-90 snails. Finally, hemocyte responses against some small primary sporocysts occurred at 1 and 3 days post-exposure (DPE) in all 3 strains, but in 2 of 5 M line a response also occurred against large primary sporocysts at 6 DPE. Thus, based on infection prevalence and tissue responses, compatibility with NMRI S. mansoni is lowest in M line, whereas UML and NMRI show the same degree of compatibility, despite decades of maintenance of this parasite strain in NMRI snails. The elevated mitotic response in the APO of M line and NMRI snails suggests that a response of the IDS can occur even in a compatible host-parasite relationship.