Podophyllotoxin derivatives containing structural modifications at C-4 and in the methylenedioxy A ring, lactone D-ring, and phenyl E-ring have been tested for inhibition of HIV replication. The four most promising compounds (6, 7, 8, and 19), with the methylenedioxy A-ring opened and methylated and the 4'-position demethylated, had EC50's less than 0.001 ktM and therapeutic indices greater than 120. © 1997 Elsevier Science Ltd.