Background: Numerous studies have revealed widespread clinician frustration with the usability of electronic health records (EHRs) that is counterproductive to adoption of EHR systems to meet the aims of health-care reform. With poor system usability comes increased risk of negative unintended consequences. Usability issues could lead to user error and workarounds that have the potential to compromise patient safety and negatively impact the quality of care.^[1] While there is ample research on EHR usability, there is little information on the usability of laboratory information systems (LISs). Yet, LISs facilitate the timely provision of a great deal of the information needed by physicians to make patient care decisions.^[2] Medical and technical advances in genomics that require processing of an increased volume of complex laboratory data further underscore the importance of developing user-friendly LISs. This study aims to add to the body of knowledge on LIS usability. Methods: A survey was distributed among LIS users at hospitals across the United States. The survey consisted of the ten-item System Usability Scale (SUS). In addition, participants were asked to rate the ease of performing 24 common tasks with a LIS. Finally, respondents provided comments on what they liked and disliked about using the LIS to provide diagnostic insight into LIS perceived usability. Results: The overall mean SUS score of 59.7 for the LIS evaluated is significantly lower than the benchmark of 68 (P < 0.001). All LISs evaluated received mean SUS scores below 68 except for Orchard Harvest (78.7). While the years of experience using the LIS was found to be a statistically significant influence on mean SUS scores, the combined effect of years of experience and LIS used did not account for the statistically significant difference in the mean SUS score between Orchard Harvest and each of the other LISs evaluated. Conclusions: The results of this study indicate that overall usability of LISs is poor. Usability lags that of systems evaluated across 446 usability surveys.