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We present Mixminion, a message-based anonymous remailer protocol with secure single-use reply blocks. Mix nodes cannot distinguish Mixminion forward messages from reply messages, so forward and reply messages share the same anonymity set. We add directory servers that allow users to learn public keys and performance statistics of participating remailers, and we describe nymservers that provide long-term pseudonyms using single-use reply blocks as a primitive. Our design integrates link encryption between remailers to provide forward anonymity. Mixminion works in a real-world Internet environment, requires little synchronization or coordination between nodes, and protects against known anonymity-breaking attacks as well as or better than other systems with similar design parameters.