This paper reports the results of an Open-Top Chambers experiment on the responses of two durum wheat cultivars (Neodur and Virgilio) exposed to two different levels of ozone (charcoal-filtered air and ozone-enriched air) and irrigation water salinity (tap water as control and a 75 mM NaCl solution once a week). The stomatal conductance of the flag leaves was measured on four dates during May. Flag leaf samples were collected to detect ozone visible leaf injuries. At the end of the growing season, the yield/biomass and grain quality parameters were assessed. Saline irrigation caused significant reductions in gs, yield and grain quality in Neodur, while Virgilio was more tolerant. The yield response to ozone was almost negligible, with Virgilio, despite the higher susceptibility to visible leaf injuries, being more productive than Neodur. The responses to the combined stress were not consistent, with the main tendencies undoubtedly driven by the saline irrigation factor.