Monoclonal antibody to the mouse histocompatibility antigen, H-2k, was derivatized with palmitic acid using an activated ester of N-hydroxysuccinimide. About 70% of the resulting amphipathic antibody could be incorporated into liposomes by a detergent-dialysis method. The antibody-bound liposomes were about 900 A in diameter and were heterogeneous in terms of the number of antibody molecules per liposome. These liposomes showed specific binding affinity to mouse L-929 cells (H-2k), but not to A-31 cells (H-2d), whereas native liposomes showed no detectable binding to either cell type. The specific binding of anti-H-2k-bound liposomes to L-929 cells could be blocked by a preincubation of cells with an excess of free, underivatized anti-H-2k antibody but not by normal mouse IgG. Using a fluorescent phospholipid, liposomes containing anti-H-2k specifically labeled L-929 cells but not A-31 cells in a mixed culture. Liposomes containing normal mouse IgG did not significantly label either cell type. These results clearly demonstrated the effectiveness of the monoclonal antibody for liposome targeting.