We report a study of the factors that affect reading in Spanish, a language with a transparent orthography. Our focus was on the influence of lexical semantic knowledge in phonological coding. This effect would be predicted to be minimal in Spanish, according to some accounts of semantic effects in reading. We asked 25 healthy adults to name 2,764 mono- and multisyllabic words. As is typical for psycholinguistics, variables capturing critical word attributes were highly intercorrelated. Therefore, we used principal components analysis (PCA) to derive orthogonalized predictors from raw variables. The PCA distinguished components relating to (1) word frequency, age of acquisition (AoA), and familiarity; (2) word AoA, imageability, and familiarity; (3) word length and orthographic neighborhood size; and (4) bigram type and token frequency. Linear mixed-effects analyses indicated significant effects on reading due to each PCA component. Our observations confirm that oral reading in Spanish proceeds through spelling-sound mappings involving lexical and sublexical units. Importantly, our observations distinguish between the effect of lexical frequency (the impact of the component relating to frequency, AoA, and familiarity) and the effect of semantic knowledge (the impact of the component relating to AoA, imageability, and familiarity). Semantic knowledge influences word naming even when all the words being read have regular spelling-sound mappings.