In this study, four large pilot-scale horizontal–vertical hybrid constructed wetlands (CWs) were constructed for the tertiary treatment of effluent of North Wastewater Treatment Plant in Isfahan, Iran. The plant effluent did not meet the regulation limits of wastewater reuse for various applications (e.g., irrigation of food and non-food crops, forests and green areas, groundwater recharge, and urban reuse applications). So the hybrid CW system was set up to provide a suitable effluent for this purpose. Each hybrid unit consisted of a 100-m2 horizontal flow (HF) and a 32-m2 vertical flow (VF) subsurface CW operating in series. Three emergent plants consisting of Phragmites australis, Typha latifolia, and Arundo donax were planted in the CWs and one unit left unplanted. The filling material was fine grain from 3–7 mm. The average organic load and the average hydraulic loading rate (HLR) of the system were 15 g biochemical oxygen demand (BOD5) m−1 day−1 and 5.3 cm day−1, respectively. The k-C* first-order model constant was computed for seven physical, chemical, and microbiological parameters—BOD5, chemical oxygen demand (COD), total suspended solids (TSS), NO3-N, NH4-N, total phosphorus (TP), and fecal coliforms—based on the influent/effluent concentration data for estimation of required surface area of full-scale CWs in the future. The results of 12-month sampling showed that the hybrid HF-VF CWs are highly efficient in removing of the BOD5 (85 % medium), COD (80 % medium), TSS (79 % medium), NH4-N (78 % medium), TP (74 % medium), and fecal coliforms (99 % medium). Also, there were no significant differences between various planted hybrid CWs in removal efficiency and first-order model constant for BOD5, COD, TSS, and coliforms, nor were there significant differences between planted and unplanted CWs for these parameters. But, for nutrients, the removal efficiencies of planted CWs were higher than those of control CW during the operation time. Among the CWs, the Phragmites showed the best efficiency for removal of nutrients followed by Arundo. It was observed that the removal efficiencies in HFCWs were higher than those in VFCWs due to longer hydraulic retention time (HRT), but for coliform removal, the VFCWs showed a higher efficiency. The effluent quality met the requirements for its reuse in various applications, but bacterial contents were equal to levels that permit the reuse of effluent in the non-food crop, forest and other green area irrigation, groundwater recharge, and some urban applications with restricted public exposure. The results of this pilot-scale research study showed that the performance of a single HFCW was probably not sufficient to achieve a suitable water quality for reuse of effluents and the hybrid CWs are more efficient and feasible systems for this purpose.