The present study aimed to evaluate the persistent efficacy of a 3.5% doramectin(*) (700 μg/kg) formulation compared to 3.15% ivermectin(**) (630 μg/kg) treatment, administered subcutaneously at a dose of 1 mL/50 kg body weight in cattle experimentally infected with gastrointestinal nematodes. Seventy-two male crossbred Holstein cattle that were negative for helminth infection were divided into nine groups. Treatments of 3.5% doramectin (Groups 2, 4, 6 and 8) and 3.15% ivermectin (Groups 3, 5, 7 and 9) were administered on days 49, 42, 35 and 28 prior to challenge with infectious nematode larvae (L3). Animals in the control group (Group 1) received saline solution on day 49 before challenge. Beginning on day zero, each animal received 50 mL orally of a mixed culture containing approximately 3,000 third stage larvae (L3) of Haemonchus (60%), Oesophagostomum (20%), Cooperia (15%) and Trichostrongylus (5%) for seven consecutive days, resulting in a total challenge of 21,000 larvae/animal. Due to the large number of cattle, autopsies were performed between days 28 and 35 after the last day of inoculation. The formulation containing doramectin (700 mcg/kg) achieved persistent efficacy against H. placei and C. punctata for 49 and 35 days, respectively. The persistent efficacy of ivermectin (630 mcg/kg) against H. placei lasted for 49 days, but this treatment was ineffective against C. punctata. Both formulations demonstrated persistent efficacy against T. axei for 49 days. The persistent efficacy of doramectin (700 mcg/kg) and ivermectin (630 mcg/kg) lasted for 49 and 42 days against O. radiatum, respectively.