RNA Antisense Purification with Mass Spectrometry (RAP-MS) is a method to purify a lncRNA complex in vivo and identify the direct interacting proteins by quantitative mass spectrometry. RAP-MS uses UV crosslinking to create covalent linkages between directly interacting RNA and protein and purifies lncRNAs in denaturing conditions to disrupt non-covalent interactions. This UV-crosslinking and denaturing approach, which is utilized by methods such as CLIP, is known to identify only direct RNA-protein interactions and to separate interactions that are crosslinked in the cell from those that merely associate in solution. The RAP-MS method uses long biotinylated antisense probes, which form very stable RNA-DNA hybrids, and therefore can be used to purify lncRNA complexes in denaturing and reducing conditions. The RAP-MS method has been optimized to achieve higher yields and enrichment levels of the endogenous RNA complexes relative to our original protocol used for DNA and RNA. To achieve sensitive quantification and to distinguish between specific proteins and background proteins, RAP-MS uses Stable Isotope Labeling by Amino acids in Culture (SILAC) to label proteins and specific lncRNA captures are directly compared to a control ncRNA.