Several streptocyanine dyes were synthesized that contain polymethine chains of varying length. Their in vitro antimalarial activities were evaluated against the virulent P. falciparum parasite. In addition to the influence of polymethine chain length, the effects of structural modifications at nitrogen end groups, para substitution of the phenyl groups, and counter-anions were studied. The most potent antimalarial activities were found for heptacarbon chain streptocyanines, with an IC(50) value of 60 nM. Interestingly, most of the compounds were less cytotoxic toward the mammalian cells tested. The best selective toxicity profiles were found for pentacarbon chain streptocyanines, which have a good in vitro specificity index.