With the advent of smart grid technologies, modern Distribution Management Systems (DMSs) enable the real-time operation of advanced automation functions such as Coordinated Volt/VAr Control (CVVC). Typically, control rule-based techniques have been proposed to efficiently carry out this important function in Distribution Networks (DNs). In this paper, a novel adaptation of the clonal selection theory of immune systems (CLONALG - Clonal Selection Algorithm) is proposed for real-time optimal solution of CVVC problem in radial DNs composed of multiple control equipment. To do this, a Software-in-the-Loop (SIL) strategy is developed, through the use of the Real-Time Digital Simulator (RTDS) and Matlab® program. Implementation details of the referred strategy and the corresponding adaptation of the CLONALG-based CVVC are discussed in this paper. Simulations results demonstrated that the proposed adaptation of the CLONALG technique is suitable to solve the CVVC problem in a maximum time of less than 10 min, in accordance with the Brazilian electric utilities’ need. On the other hand, the developed SIL strategy proved to be effective to analyzing the time domain behavior of CVVC algorithms, designed to operate in real time in a modern DMS.