Patients who read in a letter-by-letter manner can demonstrate effects of lexical variables when reading words comprised of low confusability letters, suggesting the capacity to process low-confusability words in parallel across the letters (Fiset, Arguin, & McCabe, 2006). Here a series of experiments is presented investigating letter confusability effects in MAH, a patient with expressive and receptive aphasia who shows reduced reading accuracy with longer words, and DM, a relatively "pure" alexic patient. Two rehabilitation studies were employed: (i) a word-level therapy and (ii) a letter-level therapy designed to improve discrimination of individual letters. The word-level treatment produced generalised improvement to low-confusability words only, but the serial processing treatment produced improvement on both high and low confusability words. The results add support to the hypothesis that letter confusability plays a key role in letter-by-letter reading, and suggest that a rehabilitation method aimed at reducing ambiguities in letter identification may be particularly effective for treating letter-by-letter reading.