The present study examined how word-initial letters influence lexical access during reading. Eye movements were monitored as participants read sentences containing target words. Three factors were independently manipulated. First, target words had either high or low constraining word-initial letter sequences (e.g., dwarf or clown, respectively). Second, targets were either high or low in frequency of occurrence (e.g., train or stain, respectively). Third, targets were embedded in either biasing or neutral contexts (i.e., targets were high or low in their predictability). This 2 (constraint) × 2 (frequency) × 2 (context) design allowed us to examine the conditions under which a word's initial letter sequence could facilitate processing. Analyses of fixation duration data revealed significant main effects of constraint, frequency, and context. Moreover, in measures taken to reflect "early" lexical processing (i.e., first and single fixation duration), there was a significant interaction between constraint and context. The overall pattern of findings suggests lexical access is facilitated by highly constraining word-initial letters. Results are discussed in comparison to recent studies of lexical features involved in word recognition during reading.