We examined the cognitive, language, and instructional predictors of early word-reading ability in a sample of children with Williams syndrome longitudinally. At Time 1, sixty-nine 6-7-year-olds (mean age = 6.53 years) completed standardized measures of phonological awareness, visual-spatial perception, vocabulary, and overall intellectual ability. Word-reading instruction type was classified as (systematic) Phonics (n = 35) or Other (n = 34). At Time 2, approximately 3 years later (mean age = 9.47 years), children completed a standardized assessment of single-word reading ability. Reading ability at Time 2 varied considerably, from inability to read any words to word-reading ability slightly above the level expected for age. The results of a multiple regression indicated that Time 1 word-reading instruction type, phonological awareness, and visual-spatial perception (as assessed by a matching letter-like forms measure) each explained significant unique variance in word reading at Time 2. A systematic phonics approach was associated with significantly better performance than other reading-instruction approaches. Exploratory analyses suggested that the relations between these factors were complex. Considered together, these findings strongly suggest that, in line with the Cumulative Risk and Resilience Model of reading disability, word-reading (dis)ability in Williams syndrome is probabilistic in nature, resulting from the interaction of multiple individual and environmental risk and protective factors. The results also have educational implications: early word-reading instruction for children with Williams syndrome should combine systematic phonics and phonological awareness training while also incorporating letter discrimination instruction highlighting the visual-spatial differences between similar-appearing letters.