Introduction: Huge investments have been made in implementing computerized Hospital Management Information Systems (HMIS) across the world, including developing countries. Economic evaluation studies have shown that HMIS implementations are beneficial. While measuring effectiveness, studies have compared the quality of data generated in the HMIS with paper-based systems and have shown that HMIS is more advantageous. However, not all HMIS implementations are successful. Many successful implementations are the result of a continuous process of re-engineering, with inputs obtained from the end-users at every stage of the implementation process. The aims of this study were to compare cost-effectiveness, end-user satisfaction and perspectives between HMIS and traditional paper-based system (TPBS). Materials and Methods: This cross-sectional study evaluates the HMIS in government hospitals in Tamil Nadu using a mixed method approach. The study sample included 24 hospitals (13 HMIS and 11 TPBS), and hospital staff in four professional categories (doctors, staff nurses, pharmacists and lab technicians). Results: Cost-effectiveness analysis showed that HMIS implementation has high cost and high effectiveness with an ICER value of 3301.33. The Likert scale used to measure end-user satisfaction levels found that end-users were highly satisfied with HMIS as compared to TPBS. Conclusions: The study demonstrated the high cost and high effectiveness of HMIS implementation. The ‘accuracy of data’, ‘content of the system’ and the ‘timely availability’ characteristics of HMIS were highly appreciated by the users, whereas in TPBS, the users appreciated the ‘user friendly’ nature of this system.