Two different types of derivatives of theophylline (Th-H) incorporating ethyleneoxy groups into the promoiety have been synthesized. One is a soft alkyl type where N-methyl-N-methoxyethyleneoxycarbonylaminomethyl chlorides have been used to alkylate Th-H in the 7 position. The other is in an acyl type where methoxyethyleneoxycarbonyl chlorides have been used to acylate Th-H in the 7 position. All of the prodrugs were more soluble in the lipid isopropyl myristate (IPM) than Th-H, and three were more soluble in water (AQ) than Th-H. The most water-soluble prodrug gave the highest maximum delivery of total species containing Th-H through hairless mouse skin from IPM (maximum flux, J(MMIPM))-more than seven times that of Th-H, while the other two gave more than three times that of Th-H. The acyl-type prodrugs delivered only Th-H, while the soft alkyl types delivered 60-70% Th-H plus intact prodrug. The Roberts-Sloan equation was able to predict the best performer for each type with an average of the absolute difference between the experimental log J (MMIPM) and calculated log J (MMIPM) (Δlog J (MMIPM)) of 0.253 log units. The values for the present prodrugs and previously reported prodrugs that had not been previously included in the Roberts-Sloan data base (n = 23) were included in the previous n = 71 data base to give n = 94. New coefficients for the Roberts-Sloan equation have been obtained.