The accurate prediction of pressure losses across in-duct fittings is of significance in relation to the accurate sizing and good energy efficiency of air-delivery systems. Current design guides provide design methods and data for the prediction of pressure losses only for a single and isolated fitting. This study presents an investigation of pressure losses across multiple interactive in-duct fittings in a ventilation duct. A laboratory measurement of pressure losses across one fitting and multiple fittings in a ventilation duct is carried out. The pressure loss across multiple interactive fittings is lower than that across multiple similar individual fittings, while the percentage decrease is dependent on the configuration and combination of the fittings. This implies that the pressure loss across multiple closely mounted fittings calculated by summing the pressure losses across individual fittings, as provided in the ASHRAE handbook and the CIBSE guide, is overpredicted. The numerical prediction of the pressure losses across multiple fittings using the large-eddy simulation (LES) model shows good agreement with the measured data, suggesting that this model is a useful tool in ductwork design and can help to save experimental resources and improve experimental accuracy and reliability.