A study conducted in São Paulo State, Brazil, evaluated anthelmintic resistance in sheep flocks over the past decades. The research assessed the efficacy of various anthelmintics, including albendazole, levamisole, ivermectin, monepantel, closantel, and moxidectin, against gastrointestinal nematodes such as Haemonchus contortus and Trichostrongylus colubriformis. The study involved 15 sheep flocks, with each flock divided into groups treated with different anthelmintics. Faecal egg count reduction tests (FECRT) were used to measure the effectiveness of these treatments. The results showed that multiple anthelmintic resistance was prevalent in all 15 flocks. Albendazole had an average efficacy of 40%, while monepantel showed the highest overall efficacy (79%) and was effective in five farms with efficacy ≥95%. Levamisole had an average efficacy of 48%, with two farms showing high efficacy (90% and 89%). Ivermectin and moxidectin had lower efficacies (34% and 21%, respectively). Closantel had an average efficacy of 63%. Haemonchus contortus was the most prevalent nematode, and resistance to multiple anthelmintics was observed in all flocks. The study highlights the increasing resistance of gastrointestinal nematodes to anthelmintic drugs, which has worsened over the past three decades. Despite the introduction of targeted selective treatment (TST) and other management practices, anthelmintic resistance has not improved, and in some cases, has increased. The findings suggest that sustainable and long-term strategies are needed to manage gastrointestinal nematode infections in sheep farming. The study underscores the importance of reducing anthelmintic use and implementing alternative management practices to prevent the development of resistance.A study conducted in São Paulo State, Brazil, evaluated anthelmintic resistance in sheep flocks over the past decades. The research assessed the efficacy of various anthelmintics, including albendazole, levamisole, ivermectin, monepantel, closantel, and moxidectin, against gastrointestinal nematodes such as Haemonchus contortus and Trichostrongylus colubriformis. The study involved 15 sheep flocks, with each flock divided into groups treated with different anthelmintics. Faecal egg count reduction tests (FECRT) were used to measure the effectiveness of these treatments. The results showed that multiple anthelmintic resistance was prevalent in all 15 flocks. Albendazole had an average efficacy of 40%, while monepantel showed the highest overall efficacy (79%) and was effective in five farms with efficacy ≥95%. Levamisole had an average efficacy of 48%, with two farms showing high efficacy (90% and 89%). Ivermectin and moxidectin had lower efficacies (34% and 21%, respectively). Closantel had an average efficacy of 63%. Haemonchus contortus was the most prevalent nematode, and resistance to multiple anthelmintics was observed in all flocks. The study highlights the increasing resistance of gastrointestinal nematodes to anthelmintic drugs, which has worsened over the past three decades. Despite the introduction of targeted selective treatment (TST) and other management practices, anthelmintic resistance has not improved, and in some cases, has increased. The findings suggest that sustainable and long-term strategies are needed to manage gastrointestinal nematode infections in sheep farming. The study underscores the importance of reducing anthelmintic use and implementing alternative management practices to prevent the development of resistance.