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We explore the use of signatures, i.e., partial truth tables generated via bit-parallel functional simulation, during soft error analysis and logic synthesis. We first present a signature-based CAD framework that incorporates tools for the logic-level analysis of soft error rate (x) and for signature-based design for reliability (SiDeR). We observe that the soft error rate (SER) of a logic circuit is closely related to various testability parameters, such as signal observability and probability. We show that these parameters can be computed very efficiently (in linear time) by means of signatures. Consequently, AnSER evaluates logic masking two to three orders of magnitude faster than other SER evaluators while maintaining accuracy. AnSER can also compute SER efficiently in sequential circuits by approximating steady-state probabilities and sequential signal observabilities. In the second part of this paper, we incorporate AnSER into logic synthesis design flows aimed at reliable circuit design. SiDeR identifies and exploits redundancy already present in a circuit via signature comparison to decrease SER. We show that SiDeR reduces SER by 40% with only 13% area overhead. We also describe a second signature-based synthesis strategy that employs local rewriting to simultaneously improve area and decrease SER. This technique yields 13% reduction in SER with a 2% area decrease. We show that combining the two synthesis approaches can result in further area-reliability improvements.