The goals of our study were to determine the predictive value and usability of an audience response system (ARS) as a knowledge assessment tool in an undergraduate medical curriculum. Over a three year period (2006-2008), data were collected from first year didactic blocks in Genetics/Histology and Anatomy/Radiology (n = 42-50 per class). During each block, students answered clinically oriented multiple choice questions using the ARS. Students' performances were recorded and cumulative ARS scores were compared with final examination performances. Correlation coefficients between these variables were calculated to assess the existence and direction of an association between ARS and final examination score. If associations existed, univariate models were then constructed using ARS as a predictor of final examination score. Student and faculty perception of ARS difficulty, usefulness, effect on performance, and preferred use were evaluated using a questionnaire. There was a statistically significant positive correlation between ARS and final examination scores in all didactic blocks and predictive univariate models were constructed for each relationship (all P < 0.0001). Students and faculty agreed that ARS was easy to use and a reliable tool for providing real-time feedback that improved their performance and participation. In conclusion, we found ARS to be an effective assessment tool benefiting the faculty and the students in a curriculum focused on interaction and self-directed learning.