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This paper describes a systematic method for identification of environmentally friendly, high performance substitute materials for application in manufacturing and facilities operations. Most manufacturing depends critically on a variety of materials used in production and facilities operations. Because of environmental regulations, many of these materials have become expensive or unavailable. By use of the Systematic Materials Substitution (SyMS) process, superior replacement materials can be identified. Examples of successful use of the SyMS process are given, including a drop-in replacement thrust vector control fluid to replace Halon 2402 in the Minuteman Stage II, a drop-in Halon 1301 replacement for use in unoccupied areas, high performance refrigerants for replacement of R-12 and R-134a, and environmentally friendly, nonflammable solvents.