Vector signaling codes are synergistically combined with multi-level signaling, the increased alphabet size provided by the multi-level signaling enabling a larger codeword space for a given number of symbols, at the cost of reduced receiver detection margin for each of the multiple signal levels. Vector signaling code construction methods are disclosed in which code construction and selection of multi-level signal levels are coordinated with the design of an associated receive comparator network, wherein modified signal levels encoded and emitted by the transmitter result in increased detection margin at the receive comparators.