Amphotericin B (AmB) and clofazimine are potent drugs hindered by their low water solubilities and their toxicities. Carriers able to increase their apparent water solubilities are needed for these drugs and for other molecules with similar properties. Random amphiphilic copolymers derived from poly(dimethylmalic acid) were obtained using different hydrophobization ratios and side group sizes. Apparent water solubilities of pyrene, clofazimine, and AmB were increased up to 10 000, 20 000 and 1000 times, respectively, in aqueous solutions containing these polymers. The presence of sodium chloride in polymer solution increased pyrene solubility but decreased the solubilities of clofazimine and AmB, compared to the salt-free solutions. Synergy between hydrophobic and electrostatic interactions was observed for polar and cationic molecules. Degradation studies showed that the examined polymers were degradable, but none of them were totally degraded in 28 days. These polymers could be used as a new tool for drug solubilization.