Background: Gastrointestinal nematodes are parasites that commonly infect dogs, and infections can be subclinical or may cause considerable clinical disease. Some species are zoonotic and may also cause clinical disease in humans. Year-round treatment of dogs is recommended to eliminate existing infections, which also indirectly reduces the potential for subsequent human exposure to zoonotic species. Here we present two studies that evaluated the safety and efficacy of a novel chewable oral tablet containing sarolaner, moxidectin and pyrantel against gastrointestinal nematode infections in dogs presented as veterinary patients in Europe and the USA. Methods: Dogs naturally infected with Toxocara canis, Toxascaris leonina, Ancylostoma caninum and/or Uncinaria stenocephala were enrolled in the European study, and dogs naturally infected with T. canis were enrolled in the USA study. The animals were treated once orally with Simparica Trio ™ tablets to provide 1.2-2.4 mg/kg sarolaner, 24-48 µg/kg moxidectin and 5-10 mg/kg pyrantel (as pamoate salt) or with a commercially available product according to the label directions as positive control. Efficacy was based on the post-treatment reduction in geometric mean egg counts (per gram feces) 7 or 10 days after treatment compared to pre-treatment egg counts. Results: Simparica Trio ™ was well tolerated in both studies. In the European study, geometric mean egg counts for T. canis, T. leonina, A. caninum and U. stenocephala were reduced by ≥ 98.3% in the Simparica Trio ™ group and by ≥ 97.4% in the afoxolaner + milbemycin oxime group. In the USA study, geometric mean egg counts for T. canis were reduced by 99.2% in the Simparica Trio ™ group and by 98.6% in the ivermectin + pyrantel group. In the USA study, 48 and 10 dogs in the Simparica Trio ™ and the ivermectin + pyrantel group, respectively, were co-infected with A. caninum and the reduction in the post-treatment mean fecal egg counts were 98.6% and 74.7%, respectively.