Background: Electronic health records (EHRs) are expected to provide many clinical and organizational benefits. Simultaneously, the end users may face unintended consequences, such as stress and increased cognitive workload, due to poor EHR usability. However, whether the effects of usability depend on end user characteristics, such as career stage or age, remains poorly understood. Objective: The objective of this study was to examine the associations of EHR usability and user age with stress related to information systems and cognitive failures among registered nurses. Methods: A cross-sectional survey design was employed in Finland in 2017. A total of 3383 registered nurses responded to the nationwide electronic survey. Multiple linear regression was used to examine the associations of EHR usability (eg, how easily information can be found and a patient’s care can be documented) and user age with stress related to information systems and cognitive failures. Interaction effects of EHR usability and age were also tested. Models were adjusted for gender and employment sector. Results: Poor EHR usability was associated with higher levels of stress related to information systems (β=.38; P<.001). The strength of the association did not depend on user age. Poor EHR usability was also associated with higher levels of cognitive failures (β=.28; P<.001). There was a significant interaction effect between age and EHR usability for cognitive failures (β=.04; P<.001). Young nurses who found the EHR difficult to use reported the most cognitive failures. Conclusions: Information system stress due to poor EHR usability afflicts younger and older nurses alike. However, younger nurses starting their careers may be more cognitively burdened if they find EHR systems difficult to use compared to older nurses. Adequate support in using the EHRs may be particularly important to young registered nurses, who have a lot to learn and adopt in their early years of practice.