BACKGROUND: Control of soil-transmitted helminthiasis and schistosomiasis relies heavily on regular preventive chemotherapy. Monitoring drug efficacy is crucial to provide early warning of treatment failures. The World Health Organization (WHO) recommends a survey design in which only egg-positive individuals are retested after treatment. Although this practice makes more efficient use of resources, it may lead to biased drug efficacy estimates. METHODS: We performed a simulation study to assess the potential for bias when evaluating drug efficacy using the World Health Organization-recommended survey design, and to identify alternative designs for evaluating drug efficacy that are less affected by bias. These designs were also based on selection of egg-positive individuals, but involve retesting them a second time at baseline and up to 2 times at follow-up. The utility of the different designs was compared fairly by constraining them to the same budget. RESULTS: The standard procedure of selecting egg-positive individuals can introduce a substantial positive bias in drug efficacy due to regression toward the mean, particularly when infection levels or drug efficacy are low. This bias was completely eliminated by using a second baseline sample, conditionally on the first sample being excluded from analysis. Precision of estimates can be improved by increasing the number of thick smears and/or samples per person at follow-up, despite fewer individuals being tested within the same budget. CONCLUSIONS: We present optimized survey designs to monitor drug efficacy in field settings, which are highly relevant for sustained control of soil-transmitted helminths and schistosomiasis, as well as onchocerciasis and lymphatic filariasis.