The epipodophyllotoxin derivative VP 16–213 (NSC 141540), an antineoplastic agent of high activity against transplantable leukemia in mice and of proven activity in human tumours, was studied in combination therapy with actinomycin D, 1,3-bis( 2-chloro-ethyl)- 1-nitrosourea (BCNU), cyclophosphamide (CTX), cytosine arabinoside, daunorubicin, 5-fluorouracil, 6-mercaptopurine, methotrexate or vincristine against L 1210 leukemia in mice. With one treatment on day 1 after transplantation, the therapeutic results of the combination of VP 16–213 with actinomycin D, cytosine arabinoside, daunorubicin, 5-fluorouracil, 6-mercaptopurine, methotrexate and vincristine, were in the same range or inferior to the effect of the single agents. Combination of VP 16–213 with CTX or BCNU led to remarkably good results, which were of the “more than additive” type. Thus, in equitoxic doses, for example, the combination of VP 16–213+CTX (ratio 1:1) at the 0·5 ld 10 level gave 75% cures compared with 5% for VP 16–213 alone and 0% for CTX. When treatment was started on day 6 after transplantation, no advantage of the VP 16–213+CTX combination could be demonstrated, while the VP 16–213+BCNU combination still proved superior to the single agents, with respect to increase in life-span and cure rate.