Assessing users’ satisfaction with the user interface of Healthcare Information System in order to determine their acceptance rate should be highlighted, especially at the early stages of its implementation. This study aimed to evaluate the users’ satisfaction with Social Security Electronic System (SSES), as a widely used HIS in Iran. The population of this study composed of 327 users among whom 176 were randomly selected. An adapted version of Computer System Usability Questionnaire (CSUQ) was used for collecting data. Data were analyzed using t-test, ANOVA, Spearman, Man Whitney U, and Kruskal-Wallis. In general, 140 subjects answered the questionnaire. The users’ mean scores of satisfaction with different aspects of usability and their overall satisfaction were 56.00 ± 13.00 and 3.01 ± 1.15, respectively, indicating a medium satisfaction. Overall satisfaction and satisfaction with different aspects of usability had no significant relationship with gender, age, education degree, and working experience with computers (p > 0.05). No significant relationship was observed between overall satisfaction and working experience with SSES (p > 0.05). However, the users’ satisfaction with different aspects of usability was significantly related to experience with HISs and SSES (p < 0.05). In addition, the overall satisfaction was significantly related to experience with HISs (p < 0.05). Based on the results, the users were relatively satisfied with the system. Thus, a user centered design is recommended to improve satisfaction by addressing several modifications such as providing an easier documentation process, using lower keystrockes and fewer screens, displaying appropriate messages, providing pop-ups, guiding the users, correcting the errors, and adding search functionalities.