In an experimental study we explored the role of word frequency and orthographic constraints in the reading of Dutch bisyllabic words. Although Dutch orthography is highly regular, several deviations from a one-to-one correspondence occur. In polysyllabic words, the grapheme E may represent three different vowels: /ε /, /e/, or /œ /. In the experiment, skilled adult readers were presented lists of bisyllabic words containing the vowel E in the initial syllable and the same grapheme or another vowel in the second syllable. We expected word frequency to be related to word latency scores. On the basis of general word frequency data, we also expected the interpretation of the initial syllable as a stressed /e/ to be facilitated as compared to the interpretation of an unstressed /œ /. We found a strong negative correlation between word frequency and latency scores. Moreover, for words with E in either syllable we found a preference for a stressed /e/ interpretation, indicating a lexical frequency effect. The results are discussed with reference to a parallel dual-route model of word decoding.