Site-specific 2′-methylseleno RNA labeling is a promising tool for tackling the phase problem in RNA crystallography. We have developed an efficient strategy for crystallization and structure determination of RNA and RNA/protein complexes based on preliminary crystallization screening of 2′-OCH₃-modified RNA sequences, prior to the replacement of 2′-OCH₃ groups with their 2′-SeCH₃ counterparts. The method exploits the similar crystallization properties of 2′-OCH₃- and 2′-SeCH₃-modified RNAs and has been successfully validated for two test cases. In addition, our data show that 2′-SeCH₃-modified RNA have an increased resistance to X-ray radiolysis in comparison with commonly used 5-halogen-modified RNA, which permits collection of experimental electron density maps of remarkable quality.