Several different computational problems have been solved using DNA as a medium. However, the DNA computations that have so far been carried out have examined a relatively small number of possible sequence solutions in order to find correct sequence solutions. We have encoded a search algorithm in DNA that required the evaluation of >16 000 000 possible sequence solutions in order to find a single, correct sequence solution. Experimental evaluation of the search algorithm revealed bounds for the accuracies of answers to other large, computationally complex problems and suggested methods for the optimization of DNA computations in general. Short oligonucleotide substrates performed substantially better than longer substrates. Large, computationally complex problems whose evaluation requires hybridization and ligation can likely best be encoded and evaluated using short oligonucleotides at mesophilic temperatures.