Several studies have shown that cognitive integration of basic and clinical sciences supports diagnostic reasoning in novices; however, there has been limited exploration of the ways in which educators can translate this model of mental activity into sound instructional strategies. The use of "self-explanation" during learning has the potential to promote and support the development of integrated knowledge by encouraging novices to elaborate on the causal relationship between clinical features and basic science mechanisms. To explore the effect of this strategy, we compared diagnostic efficacy of teaching students (n = 71) the clinical features of four musculoskeletal pathologies using either (1) integrated causal basic science descriptions (BaSci group); (2) integrated causal basic science descriptions combined with self-explanation prompts (SE group); (3) basic science mechanisms segregated from the clinical features (SG group). All participants completed a diagnostic accuracy test immediately after learning and 1-week later. The results showed that the BaSci group performed significantly better compared to the SE (p = 0.019) and SG groups (p = 0.004); however, no difference was observed between the SE and SG groups (p = 0.91). We hypothesize that the structure of the self-explanation task may not have supported the development of a holistic conceptual understanding of each disease. These findings suggest that integration strategies need to be carefully structured and applied in ways that support the holistic story created by integrated basic science instruction in order to foster conceptual coherence and to capitalize on the benefits of cognition integration.