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In this paper, the simulation of the performance of solar-assisted heating and cooling systems is analyzed. Three different plant layouts are considered: (i) the first one consists of evacuated solar collectors and a single-stage LiBr–H2O absorption chiller; here in order to integrate the system in case of insufficient solar radiation, an electric water-cooled chiller is activated; (ii) configuration of the secondly considered system is similar to the first one, but the absorption chiller and the solar collector area are sized for balancing about 30% of the building cooling load only; (iii) the layout of the thirdly considered system differs from the first one since the auxiliary electric chiller is replaced by a gas-fired heater. Such system configurations also include: circulation pumps, storage tanks, feedback controllers, mixers, diverters and on/off hysteresis controllers. All such devices are modelled for maximizing the system energy efficiency. In order to simulate the systems’ performance for dynamic heating/cooling loads, a single-lumped capacitance building is also modelled and implemented in the computer code. A cost model is also developed in order to calculate the systems’ operating and capital costs. All the models and the relative simulations are carried out by TRNSYS. A design of experiment procedure is also included. By such tool the effects of the system operating parameters’ variation on the relative energy efficiency are analyzed. In addition, the set of synthesis/design variables maximizing the system’s energetic performance can be also identified. The annual primary energy saving is chosen as the optimization objective function, whereas collector slope, pump flows, set-point temperatures and tank volume are selected as optimizing system design variables. A case study was developed for an office building located in South Italy. Here, the energetic and the economic analysis for all the three considered system layouts are carried out. The simulations’ results are referred to both the initial and the optimized systems configurations. The highest primary energy saving vs. the reference traditional HVAC system is reached by the first considered system layout. The economic performance of the investigated solar heating/cooling systems is still unsatisfactory. The economical profitability of the considered solar heating and cooling systems can be improved only by significant public finding. From this point of view, the best results were achieved by the second above mentioned system configuration.