The impact of a previously successful or unsuccessful experience on the subsequent acquisition of a related task is not well understood. The nature of past experience may have even greater impact in individuals with learning deficits, as their cognitive processes can be easily disrupted. Mice with a targeted disruption of the α and δ isoforms of the cAMP-response element-binding protein (CREB) gene (CREBαδ--deficient mice) have a genetic vulnerability to impaired learning and memory that is highly influenced by experimental conditions. Thus, we studied the impact of prior successful and unsuccessful experiences on the degree to which CREBαδ--deficient mice exhibit impaired spatial learning and memory in the Morris water maze (MWM). In Experiment 1, we replicated the cognitive deficit of CREBαδ--deficient mice when given two trials per day with a 1-min intertrial interval (MWM2), and labeled this experience as a “failure.” We rescued the deficit using four trials per day with a 3- to 5-min intertrial interval (MWM4) and labeled this experience a “success.” In Experiment 2, a new, naive set of wild-type (WT) and CREBαδ--deficient mice were randomly assigned to one of two sequence protocols to assess the influence of a success or a failure on subsequent performance. In Group 1, mice were first exposed to the MWM4 condition, followed by the more difficult MWM2 task. As expected, CREBαδ--deficient mice performed well in the MWM4; they also performed well during reversal testing (MWM4R) where the goal location is changed. With this initial successful learning experience, the CREBαδ--deficient mice then performed as well as WT mice in the MWM2, the condition in which they are known to be impaired. In contrast, CREBαδ--deficient mice in Group 2 had an unsuccessful experience when first exposed to the MWM2 condition, and then also showed impairment in the MWM4, the condition in which they would normally perform well. This deficit was amplified when CREBαδ--deficient mice were then tested in the reversal test. Sex differences in learning among CREBαδ--deficient mice were amplified upon exposure to an unsuccessful learning experience. These data indicate that, under conditions of cognitive impairment, past experience can—depending on its nature—significantly facilitate or hinder future performance.