Grammatical and vocabulary knowledge (i.e., breadth and depth) are widely acknowledged as key predictors of reading comprehension in a second language (L2). However, it remains unclear how different aspects of vocabulary depth may independently contribute to L2 reading comprehension and how learners' proficiency may moderate the relative contributions of vocabulary knowledge. Based on the Lexical Quality Hypothesis and the Reading Systems Framework, this study investigated 238 L2 Chinese learners who were college-level students in China, using a set of reading-related tasks. The results showed that (1) vocabulary breadth and grammatical knowledge independently contributed to L2 reading comprehension with grammatical knowledge being a more deciding factor; (2) different aspects of vocabulary depth (i.e., polysemy and synonymy), over and above vocabulary breadth and grammatical knowledge, played an independent role; and (3) more importantly, lower-proficiency learners relied more on vocabulary breadth whereas higher-proficiency learners made more use of vocabulary depth during text-level comprehension.