The therapeutic efficacy of 20(s)-camptothecin (CPT) is limited in humans by the instability of the active lactone form due to preferential binding of the carboxylate to serum albumin and by difficulty in formulation. Formation of an ester bond with an amino acid via the hydroxyl group at carbon 20 of CPT stabilizes the lactone. Linking CPT to a high molecular weight (MW) anionic polymer enhances solubility and improves distribution to the tumor through enhanced permeability and retention (EPR effect). Poly-(L-glutamic acid) (PG) is an anionic homo-polymer that can theoretically bind one molecule of a drug via the gamma carboxylic acid of each monomeric subunit. It has been used to make a water-soluble PG-paclitaxel conjugate currently in Phase II clinical trials that contains 37% paclitaxel by weight and is administered in a 10 min infusion without pre-medication. We evaluated the anti-tumor activity of PG conjugates of CPT after a single intraperitoneal injection using subcutaneous murine B-16 melanoma tumor growth as an indicator. Interposition of a glycine (gly) linker allowed CPT loading up to 50% w/w on the polymer. Increasing the PG MW from 33 to 49 kDa enhanced the efficacy without altering the maximum tolerated dose (MTD). In athymic mice bearing ectopic human colon or lung tumors, efficacy was enhanced compared to free camptothecin. Thus, as with paclitaxel, conjugation of CPT to PG enhanced pharmaceutical properties and preclinical efficacy.