Membrane scaling constrains the operation of Reverse Osmosis (RO) forcing low water recovery, increasing brine amount and disposal cost. A high water recovery hybrid system (without antiscalants) was designed and simulated for desalination of Colorado River (CR) water (TDS = 941 mg/L) at the same capacity as the Yuma plant (96 Mgpd). The hybrid system incorporates ion exchange (IEX) water softening of Primary RO (PRO) retentate before the water is sent to Secondary RO (SRO). pH adjustment and heating of the concentrate from SRO is done before it is sent to an optional Tertiary RO (TRO). IEX treatment helped remove the scale causing precursors like Ba2+, Ca2+ and Mg2+ while pH adjustment and heating partially alleviated the problem of silica scaling allowing a maximum recovery of 96.4% with the PRO-IEX-SRO-Heat-TRO sequence. Use of concentrate from the last RO for IEX regeneration eliminates need for regeneration chemicals. Optimal RO configurations that minimize total annualized cost were determined by formulating the design as a mixed-integer nonlinear programming (MINLP) problem. Optimal process schemes were identified for different brine disposal costs. Reductions in product water cost of 75% and 50% were attained at high and low brine disposal costs, respectively. (C) 2011 Elsevier B.V. All rights reserved.