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This work studied a number of selected difficult water sample matrices. Perchlorate in these samples, and fortified samples, were analyzed by using three different methods, which include US ENvironmental Protection Agency Methods 314.0 and 331.0 and an in-house reversed-phase LC/ESI/MS/MS method. The research addressed the following issues: comparability of the analytical results provided by these methods; method detection limits (MDLs) and practical minimum reporting levels (MRLs); accuracy and precision; effectiveness of sample pretreatment with cartridges used to reduce matrix effects; and, cost analysis. The results were expected to be helpful for the selection of analytical methods for perchlorate monitoring under the UCMR 2. Includes 12 references, tables.