Although most eukaryotic mRNAs require a 5ʹ-cap for translation initiation, some can also be translated through a poorly studied cap-independent pathway. Here we developed a circRNA-based system and unbiasedly identified more than 10,000 sequences in the human transcriptome that contain Cap-independent Translation Initiators (CiTIs). Surprisingly, most of the identified CiTIs are located in 3ʹUTRs, which mainly promote translation initiation in mRNAs bearing highly structured 5ʹUTR. Mechanistically, CiTI recruits several translation initiation factors including eIF3 and DHX29, which in turn unwind 5ʹUTR structures and facilitate ribosome scanning. Functionally, we showed that the translation of HIF1A mRNA, an endogenous DHX29 target, is antagonistically regulated by its 5ʹUTR structure and a new 3ʹ-CiTI in response to hypoxia. Therefore, deletion of 3ʹ-CiTI suppresses cell growth in hypoxia and tumor progression in vivo. Collectively, our study uncovers a new regulatory mode for translation where the 3ʹUTR actively participate in the translation initiation.