The role of cholinergic basal forebrain (CBF) neurons in mnemonic behaviors was investigated using the immunotoxin 192IgG-saporin. We assessed two routes of immunotoxin administration: intracerebroventricular (ICV) and intraparenchymal (INTRA). INTRA lesions of the medial septum (MS) and/or the nucleus basalis magnocellularis (NBM) were compared with ICV-lesions, INTRA-phosphate-buffered saline injected, and naive controls. The INTRA-NBM/MS and ICV NBM/MS lesions produced a similar depletion of choline acetyltransferase activity of 80% across all CBF projections. Water maze performance was similarly impaired for ICV- and INTRA-NBM/MS animals during various phases of testing, whereas animals with individual lesions of the NBM or MS performed at the level of controls. In contrast to the allocentric demands of water maze performance, the egocentric-based T-maze task revealed a vast group difference between the ICV- and the INTRA-NBM/MS animals. INTRA-NBM/MS animals showed a severe deficit in the non-match- and match-to-position version, whereas again, animals with single lesions were unimpaired. In addition, a dichotomy between animals with complete cholinergic deafferentation was observed in the inhibitory avoidance task. ICV-NBM/MS showed a diminished retention for the aversive stimulus while the INTRA-NBM/MS animals remembered well. During plus maze testing, only the INTRA-NBM/MS animals had a reduced level of anxiety. Although non-CBF regions may have been differently affected by the two routes of immunotoxin administration, global measures of arousal, motivation, and motor initiation did not reveal a different behavioral pattern. Our findings suggest that a dynamic interplay exists between the degree of cholinergic deficit and task demands revealing different types of mnemonic impairments.