The purpose of this study was to investigate the role of breadth and depth of vocabulary knowledge in reading comprehension at Debre Markos University. A quantitative approach was taken to gather and analyze the data. Out of 235 students learning at the college, 61 samples were taken randomly. To investigate their knowledge of vocabulary breadth, the Vocabulary Levels Test (VLT) was employed. The Depth of Vocabulary Knowledge (DVK) test was utilized to investigate the depth of vocabulary knowledge. The reading section of the Test of English as a Foreign Language (TOFEL) was used to determine the reading comprehension performance of the students. Pearson Product-moment correlation was used to examine the relationship between vocabulary knowledge (breadth and depth) and reading comprehension. In addition, to find out which aspect of vocabulary knowledge best explains reading comprehension, Standard Multiple Regression was employed. The data were analyzed using SPSS (version 21). The findings suggest that there was a significant strong positive relationship between knowledge of vocabulary breadth and reading comprehension (r = 0.73, n = 61, P, =0.000 < 0.05). Besides, the result reveals that there was a significant strong positive relationship between knowledge of vocabulary depth and reading comprehension (r = 0.60, n = 61, P, =0.000 < 0.05). The finding also shows that vocabulary breadth and depth together were able to predict respondents' reading comprehension. However, vocabulary breadth (Beta =0.58) had a more unique explanatory power than knowledge of vocabulary depth (Beta =0.315).