Co-operative co-evolution approach solves problems by breaking them into subproblems. The proposed framework for Clinical Decision Support System (CDSS) uses a co-operative coevolution approach which treats Feature Selection (FS) and Instance Selection (IS) as independent subproblems. FS and IS remove less relevant features and instances, respectively, thereby improving the overall performance of the system. In this work, both Feature and Instance selection are done using the wrapper approach, which uses co-operative co-evolution and random forest classifier. The reduced dataset is used to train a random forest classifier and this trained model helped in making clinical decisions. These decisions assist physicians as the second opinion for diagnosis and treatment. Wisconsin Diagnostic Breast Cancer (WDBC), Hepatitis, Pima Indian Diabetes (PID), Cleveland Heart Disease (CHD), Statlog Heart Disease (SHD), Vertebral Column, and Hepatocellular Carcinoma (HCC) datasets from the University of California Irvine (UCI) Machine Learning repository are used for experimentation. The proposed framework achieved an accuracy of 97.1%, 82.3%, 81.01%, 93.4%, 96.8%, 91.4%, and 72.2% for datasets WDBC, Hepatitis, PID, CHD, SHD, vertebral column, and HCC, respectively. The results prove that the CDSS-developed using co-operative coevolution can efficiently assist the physicians in decision-making. © 2020, © 2020 IETE.