This study investigated the performance of two full-scale ion exchange (IX) systems, one point-of-entry (POE) reverse osmosis (RO) system and nine point-of-use (POU) RO units for simultaneous removal of arsenic and several co-occurring contaminants from drinking water. The study was performed as part of the U.S. Environmental Protection Agency's Arsenic Treatment Demonstration Program. The IX systems, with strong base anionic (SBA) resins, effectively removed arsenic (As), nitrate (NO) and uranium (U) to below respective maximum contaminant levels and vanadium (V) and molybdenum (Mo) to below 2 μg/L. The useful run length, as determined by either 10-mg/L (as N) nitrate or 10-μg/L arsenic breakthrough, was approximately 400 bed volumes (BV) initially. However, it was decreased over time, e.g., by 15% in 13 months at one site and 33% in 7 months at another site, apparently caused by resin fouling due to the presence of 2-mg/L natural organic matter (NOM) in source waters. The use of dual resins ‒ an acrylic SBA resin underlain by a polystyrene SBA resin ‒ effectively removed NOM and allowed the system to perform at its baseline level through the 13-month study. Arsenic and nitrate peaking occurred when the resins were not regenerated timely. The removal of contaminants appeared to follow a selectivity sequence: U, Mo > V > SO > HAsO > NO > HCO. RO effectively removed arsenic, nitrate, antimony, uranium and vanadium, mostly with a >99% rejection rate. The POE RO coupled with dual plumbing (only treating a fraction of water for potable use) and POU RO in individual homes could be used as low-cost alternatives to traditional RO treatment.