Background: The HITECH act's financial incentives and meaningful use mandates have resulted in unprecedented rates of EHR and CDSS adoption. These systems are premised on evidenced-based guidelines, the standardization of care, and the reduction of subjective clinical decisions. They are designed to record clinical events, synchronize the efforts of care teams, facilitate the exchange of information, and improve the control and design of clinical processes. Knowledge workers are challenged to assimilate these changes into a deliberative and autonomous style of practice. Aims: The study examined the impact of a CDSS implementation on nurses' perceptions of their ability to perform aspects of knowledge work and on the nursing practice environment. Nurse and clinical unit characteristics were examined to identify those that predicted outcome variance. Methods: This study used The Impact of Health Information Technology (I-HIT) and The Essentials of Magnetism II (EOM II) instruments. Guided by the Quality Health Outcomes Model, this pre-post, quasi-experimental study includes t-tests, repeated measure and univariate general linear model regression analyses. Two groups comprised the convenience sample of 1,045 nurses: a paired (n=458) and independent (n=587). Results: The functionality of the CDSS was perceived to reduce nurses' ability to efficiently practice, communicate, share information, and interfered with workflow in ways that depersonalized care. Perceptions of the practice environment, interestingly, remained essentially unchanged, with slight improvements and no statistically significant declines. This included perceptions about autonomy, patient-centered values, professional satisfaction and quality care. Even though the CDSS's functionality interfered with practice, and may be poised to deemphasize subjective judgment and autonomy, nurses did not seem to reject the CDSS's ability to standardize aspects of care. This study also found that nurse and clinical unit characteristics such as clinical unit type, shift, expertise, race, and whether or not nurse education was obtained outside of the USA, explained more variance than years of experience, institutional tenure, and level of education. Conclusion: Results suggest that nursing science needs to investigate and advise the design of CDSSs, as well as, develop tactics to reap the benefits of processes and guidelines, while preserving knowledge works' emphasis on expertise, intuition, and holistic care.