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Abstract The antineoplastic activity of two ether lipid derivatives, the alkyl‐lysophospholipid derivative (ALP) ET‐18‐OCH 3 and the ether‐linked lipoidal amine CP‐46,665 was tested in a human tumor clonogenic assay (HTCA) in vitro. CP‐46,665 suppresed the colony formation of various human tumors with a slight dose response relation after 1 hr incubation and with a clear optimum (85% response rate) after continuous exposure in the higher dose range tested (10 μg/ml). ET‐18‐0CH 3 did not have substantial activity after 1 hr of incubation. However, when continuous exposure to the compound was used, ET‐18‐OCH 3 seemed to have a modest dose response effect and yielded a response in about 60% of the tumor cell samples tested in the higher dose range (10 μg/ml). Thus, both compounds have in vitro antitumor activity in the HTCA within a dose range of 1–10 μg/ml, especially during continuous exposure. The tumor specific type activity was found in breast cancer, ovarian cancer, lung cancer and mesothelioma. Both compounds caused decreases in colony formation down to the 0%, 2% and 4% levels. In a comparison of specimens in which both compounds were used, only one of five times showed a discordance in sensitivity or resistance; therefore the compounds appear similar in their in vitro activity. In a second set of experiments we tested the structure‐activity relationship among a variety of ALP in the [ 3 H]thymidine incorporation assay after incubation with HL‐60 leukemic blasts and other neoplastic cells from human origin. From these studies it can be concluded that in the ALP the alkyl linkage in the sn‐1 position is a necessary prerequisite for cytotoxicity; furthermore, in the majority of tumors tested the substitution of the sn‐2 position to prevent reacylation of the molecule is necessary for cytotoxicity.