Two of the main concerns for wastewater reuse in agricultural irrigation are environmental and human security. Different research studies and practices have been developed recently in order to quantify the risk of possible environmental contamination of surface and groundwater resources as well as the risk to public health from enteric viruses. Other, far from negligible, related issues are largely of a socio-economic and technical character. For example, the social acceptance, especially by farmers, of wastewater reclamation and reuse in agriculture is influenced by specific local cultural, religious and socio-economic conditions. Economic and technical factors should also be taken into consideration, such as the water and wastewater treatment costs, the cost of maintenance, the employment of rural labour, the structure of irrigation networks and crop patterns. In this paper, the concept of sustainability in wastewater reclamation and reuse is formulated by using a general risk analysis framework and by taking into account all the above factors. The paper suggests a methodology for sustainable wastewater reuse in agriculture by considering not only technical and economic factors, but also environmental and social risks. Alternative strategies based on different treatment and irrigation technologies are evaluated using the multicriteria decision analysis technique. The methodology is illustrated in a case study of wastewater reclamation and agricultural reuse in the city of Thessaloniki, Macedonia, Greece.