The removal efficiency of an urban wastewater treatment plant (WWTP) to obtain an effluent suitable for agriculture reuse was evaluated in a one-year period, taking into account the Italian wastewater limits and the recent European proposal for the minimum requirements water quality for agricultural irrigation. The secondary effluent of WWTP was treated by three full-scale horizontal sub-surface flow (H-SSF) constructed wetlands (CWs), working in parallel, planted with different macrophytes species, and combined with a UV device and a lagooning system running in series. The H-SSF CW system effectively reduced physico-chemical pollutants and its efficiency was steady over the investigation period, while, Escherichia coli densities always exceed the Italian limits required for wastewater reuse in agriculture. The UV system significantly reduced the microbiological indicators, eliminating E. coli, in compliance with the Italian regulation, and somatic coliphages, although a variable efficacy against total coliforms and enterococci, especially in winter season, was achieved. Although the lagooning unit provides a high removal of the main microbial groups, it did not reduce physico-chemical parameters. Even if the overall performance target, for the whole treatment chain, met the recent log reduction (≥5.0), required by the European Commission, the persistence of enterococci, especially in winter season, poses a matter of concern for public health, for the potential risk to serve as a genetic reservoir of transferable antibiotic-resistance.