Many medical schools have developed computer-based, multimedia learning environments to fill the knowledge gap and provide common cases and resources to students. However, considering that multimedia in education may impede effective learning if the characteristics of learners and tasks are not considered thoroughly in instructional design, it is critical to develop a comprehensive understanding of learner characteristics in medical multimedia learning environments. Although many researchers agree that learners' prior knowledge, self-regulation, and motivation are important to explain learning processes, few studies have investigated their combined effects. Therefore, the current study examined the direct and indirect effects of medical clerkship students' prior knowledge, self-regulation, and motivation on learning performance in multimedia learning environments using structural equation modeling. The data of 386 medical clerkship students from 6 U.S. medical schools were analyzed. Students completed a prior knowledge test, the Self-Regulation Measure in Computer-assisted learning (SRMC), and motivational questionnaires (self-efficacy, goal-orientation, task value) during the first week of clerkship. From the second to the fourth week of clerkship rotation, the participants were asked to use the 45-minute Web Initiatives for Surgical Education-MD (WISE-MD) module on carotid artery disease. Right after taking the module, they completed posttest measures including the knowledge posttest and the Script Concordance test. The structural model showed that medical clerkship students' prior knowledge directly positively affected their learning outcome ([beta] = 0.422, p less than 0.001), self-efficacy ([beta] = 0.300, p less than 0.001) and performance approach goal orientation ([beta] = 0.294, p less than 0.001). The learners' self-regulation showed a significant positive direct effect on learning outcome ([beta] = 0.581, p less than 0.001). In terms of motivational constructs, learners' mastery goal orientation directly affec their learning outcome ([beta] = 0.358, p = 0.006). However, inconsistent with the hypothesis, learners' performance approach goal orientation showed a significant negative direct effect on learning outcome ([beta] = -0.261, p = 0.024), and performance avoidance goal orientation had a significant positive effect on learning outcome ([beta] = 0.259, p = 0.010). The findings were discussed to develop a more comprehensive understanding of the role of individual characteristics in medical multimedia learning environments. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://bibliotheek.ehb.be:2222/en-US/products/dissertations/individuals.shtml.