Purpose: The efficacy of drug delivery systems can be enhanced by making them target specific via the attachment of various ligands. We attempted to enhance tumor accumulation and therapeutic effect of doxorubicin-loaded, long-circulating, polyethylene glycol–coated liposomes (Doxil, ALZA Corp.) by coupling to their surface the anticancer monoclonal antibody (mAb) 2C5 with nucleosome-restricted activity that can recognize the surface of various tumors but not normal cells and specifically targets pharmaceutical carriers to tumor cells in vitro and in vivo. Following earlier in vitro results with various cancer cell lines, the mAb 2C5 liposomes were studied in vivo versus plain and nonspecific-IgG liposomes. Experimental Design: Antibody coupling to Doxil was done via the “postinsertion” technique. Using ¹¹¹In-labeled liposomes, the tissue biodistribution and pharmacokinetic profile were studied, as well as their accumulation in tumors in mice, followed by the whole-body γ-scintigraphic imaging. Therapeutic efficacy of mAb 2C5–targeted Doxil versus nonspecific IgG–modified and original Doxil controls was followed by registering live tumor growth and determining tumor weights upon mice sacrifice. Results: mAb 2C5–targeted liposomes showed enhanced accumulation in tumors, and the in vivo therapeutic activity of the mAb 2C5–Doxil treatment was found to be significantly superior, resulting in final tumor weights of only 25% to 40% compared with all Doxil control treatments, when tested against the s.c. primary murine tumors of 4T1 and C26 and human PC3 tumor in nude mice. Conclusions: Our results showed the remarkable capability of 2C5-targeted Doxil to specifically deliver its cargo into various tumors, significantly increasing the efficacy of therapy.