Background Medication dose adjustment is crucial for patients with renal dysfunction (RD). The assessment of renal function is generally mandatory; however, the renal function may change during the hospital stay and the manual assessment is sometimes challenging. Objective We developed the clinical decision support system (CDSS) that provided a recommended dose based on automated calculated renal function. Methods We conducted a prospective cohort study in a single teaching hospital in Japan. All hospitalized patients were included except for obstetrics/gynecology and pediatric wards between September 2013 and February 2015. The CDSS was implemented on December 2013. Renal and hepatic dysfunction (HD) were defined as changes in the estimated glomerular filtration rate (eGFR) and alanine aminotransferase or alkaline phosphatase levels based on these measurements during hospital stay. These measurements were obtained before (phase I), after (phase II), and 1 year after (phase III) the CDSS implementation. Results We included 6,767 patients (phase I: 2,205; phase II: 2,279; phase III: 2,283). The patients' characteristics were similar among phases. Changes in eGFR were similar among phases, but the incidence of RD increased in phase III (phase I: 228 [10.3%]; phase II: 260 [11.4%]; phase III: 296 [13.0%], p = 0.02). However, the differences in incidences of RD were not statistically significant after adjusting for eGFR at baseline and age. The incidences of HD were also similar among phases (phase I: 175 [13.2%]; phase II: 171 [12.9%]; phase III: 167 [12.2%], p = 0.72). Conclusion The CDSS implementation did not affect the incidence of renal and HD and changes in renal and hepatic function among hospitalized patients. The effectiveness of the CDSS with renal-guided doses should be investigated with respect to other endpoints.