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Lipophilic 6-chloro-2',3'-dideoxyguanosine (6-Cl-ddG) was evaluated for its improved lymph node delivery by comparison with the parental nucleoside (ddG) in vitro and in vivo. The in vitro studies with rat plasma, lymph node homogenate and stomach content indicated that 6-Cl-ddG converted to ddG more effectively in the lymph node homogenate and that 6-Cl-ddG was more stable than ddG in the stomach content. In an in vivo study, plasma and lymph nodes were collected from rats after a subcutaneous or oral administration of 6-Cl-ddG or ddG. With the subcutaneous administrations of the drugs, the area under the concentration time-curve (AUC) value in the plasma for converted ddG following a 6-Cl-ddG administration was less than half the value for ddG following a ddG administration but the converted ddG AUC values in the lymph nodes due to 6-Cl-ddG administration were 1.4- to 2.0-fold higher than the ddG AUC values due to ddG administration. Moreover, with the oral administrations, the converted ddG AUC value in plasma after a 6-Cl-ddG administration was 3-fold higher than ddG after a ddG administration, and high levels of converted ddG were detected in the lymph nodes, but no ddG was detected in the lymph node following ddG administration. These results suggest that lipophilic 6-Cl-ddG is a useful prodrug for delivering ddG into the lymph nodes by oral administration.