Previous neuroimaging research revealed a small area in the inferior occipito–temporal cortex (VWFA), which seems to be involved in recognition of written words. The specialized response of the VWFA to words could result from repeated exposure to print in the course of functional fine-tuning of the brain. Research with bilingual speakers holds promise in helping to reveal response properties of the VWFA by assessing its sensitivity to language proficiency, word-form similarity, and meaning overlap across two languages. Using fMRI, we compared VWFA activity for cognate and homograph prime-target pairs in a group of fluent Spanish–English speakers. Cognates share form and meaning in two languages, while homographs only share form. Relative to baseline, the VWFA showed repetition suppression to pairs of homographs, but not to pairs of cognates, suggesting that this area is sensitive to word meaning. The different response to cognates and homographs was only observed when English was the prime language and Spanish was the target language. To help explain this result we compared patterns of effective connectivity between the VWFA and other parts of the reading network implicated in semantic and phonological processing. Our neural models showed that English targets engaged a direct ventral route from the VWFA to the frontal lobe and Spanish targets engaged an indirect dorsal route. Considering that frontal cortex has been implicated in semantic processing, a direct connection to this area could signal a fast and automatic access to meaning and would facilitate early semantic influences in visual word recognition. Hum Brain Mapp 35:2543–2560, 2014. © 2013 Wiley Periodicals, Inc.