The universal use of Arabic numbers in mathematics raises a question whether these digits are processed the same way in people speaking various languages, such as Chinese and English, which reflect differences in Eastern and Western cultures. Using functional MRI, we demonstrated a differential cortical representation of numbers between native Chinese and English speakers. Contrasting to native English speakers, who largely employ a language process that relies on the left perisylvian cortices for mental calculation such as a simple addition task, native Chinese speakers, instead, engage a visuo-premotor association network for the same task. Whereas in both groups the inferior parietal cortex was activated by a task for numerical quantity comparison, functional MRI connectivity analyses revealed a functional distinction between Chinese and English groups among the brain networks involved in the task. Our results further indicate that the different biological encoding of numbers may be shaped by visual reading experience during language acquisition and other cultural factors such as mathematics learning strategies and education systems, which cannot be explained completely by the differences in languages per se .