Ribavirin is used to treat hepatitis C but causes serious hemolytic anemia. The objective of the study was to develop a ribavirin prodrug to achieve liver‐specific drug delivery and to reduce its off‐target effect in red blood cells (RBCs). The approach aimed to target the human sodium taurocholate cotransporting polypeptide (NTCP), which is a bile acid transporter predominately expressed in the liver. Six prodrugs with ribavirin conjugation at C‐3 or C‐24 of the bile acids were synthesized. In vitro uptake studies indicated that all six prodrugs were NTCP substrates. Metabolic studies in vitro indicated that ribavirin–l‐Val–glycochenodeoxycholic acid (GCDCA) was able to release ribavirin in the mouse liver S9 fraction. Additionally, in vitro studies showed that ribavirin in RBC was reduced by 16.7‐fold from prodrug compared with parent drug incubation. Moreover, almost no prodrug was present in RBC. In vivo study in mice also showed that ribavirin–l‐Val–GCDCA could provide almost the same ribavirin exposure in the liver as ribavirin administration, but with about 1.8‐fold less exposure of ribavirin in RBC, plasma, and kidney. Overall, the study suggested that ribavirin–l‐Val–GCDCA has the potential to achieve ribavirin‐specific liver delivery. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2864–2876, 2015