Bioassay screening of plant extracts can identify unique lead compounds for drug development, but the "hit rate" from random screening is very low. Targeted screening of medicinal plants has been repeatedly reported to increase the percentage of samples displaying bioactivity. Contrarily, Maranz (2012) suggested that African antimalarial plants were unsuitable sources of antimalarial drugs because high prevalence of malaria would result in rapid evolution of resistance to active compounds that directly targeted the parasite. As malaria is highly prevalent in much of Madagascar, it was of interest to determine whether Malagasy antimalarial plants would outperform randomly selected plants in conventional antimalarial assays being conducted as part of a discovery program. Of 1294 plant samples screened for antimalarial activity, 39.6% had an IC <50 μg/ml and 21.1% had an IC <20 μg/ml (the minimum to qualify as a first-pass "hit"). Ethnobotanical uses were coded at both the generic and the species level, as neither samples nor use reports in literature were always identifiable to species level. The 526 samples belonging to genera having reported uses for malaria were slightly more likely than average to display activity (44.3% with IC <50 μg/ml, p < .01; 23.2% with IC <20 μg/ml). Of these, 67 samples from individual species with documented use were still more likely to be modestly active (49.3% with IC <50 μg/ml), yet less likely to be highly active (17.9% with IC <20 μg/ml). Thus, in this specific context, ethnobotanically directed screening would not have substantially improved screening efficiency, and would have missed most of the potential hits.