Five antischistosomal compounds--hycanthone, two of its chloroindazole analogs (IA-4 and IA-4 N-oxide), oxamniquine, and metrifonate--were tested for mutagenic activity, using Salmonella typhimurium strains TA 98 and TA 100 under in vitro and in vivo (host-mediated) conditions. In all assay systems hycanthone exhibited by far the highest mutagenic potency. Although oxamniquine and metrifonate had low metagenic activity in vitro and although their administration resulted in urine of low metagenic activity, their host-mediated mutagenic activities on strain TA 100 were fairly high. Confirming earlier studies with a less sensitive Salmonella strain, TA 1535, IA-4 N-oxide was found to be less metagenic than IA-4. Orally administered IA-4 and IA-4-oxide were less mutagenic under in vivo conditions than an equal dose administered intramuscularly. By contrast, the antihistosomal activity of a given dose of each compound was the same, regardless of which of these two routes was used, suggesting that mutagenic and antischistosomal effects are produced by different metabolites. The observations reported in this paper provide additional evidence that mutagenic activities can be dissociated from desired chemotherapeutic effects by suitable structural modifications.