Relationships of electrostatic interaction and encapsulation between poly(amidoamine) (PAMAM) dendrimers and negatively charged drug molecules have been investigated by aqueous solubility and NMR ( (1)H NMR and two-dimensional nuclear Overhauser effect spectroscopy (2D-NOESY)) studies. PAMAM dendrimers significantly increased the solubilities of phenobarbital and sulfamethoxazole, but scarcely influenced those of primidone and trimethoprim. Moreover, (1)H NMR and 2D-NOESY measurements indicated that few phenobarbital or sulfamethoxazole molecules were entrapped in the cavities of low-generation dendrimers (generation 3, G3). These results suggest that external electrostatic interaction contributes more to the solubility enhancement of drugs than internal encapsulation.