Although great reductions in human schistosomiasis have been observed after praziquantel (PZQ) mass drug administration (MDA), some individuals remain infected after multiple treatments. Many MDA programs now require monitoring for drug efficacy as a key component. No molecular tools for PZQ resistance currently exist and investigations into the dose of PZQ required to kill 50% of adult worms in vivo (ED(50)) present ethical, logistical, and temporal restraints. We, therefore, assessed the feasibility and accuracy of a rapid, inexpensive in vitro PZQ test in the laboratory and directly in the field in Uganda under MDA in conjunction with highly detailed infection intensity, clearance, and reinfection data. This test strongly differentiated between subsequently cleared and uncleared infections as well as differences between parasite populations pre- and post-PZQ treatments, advocating its use for on-the-spot monitoring of PZQ efficacy in natural foci. After only a few treatments, uncleared parasites were identified to be phenotypically different from drug-sensitive parasites, emphasizing the urgent need for monitoring of these repeatedly PZQ-treated populations.