Two antivenoms are available for rattlesnake envenomations in the U.S., Fab (CroFab®, BTG, UK), and F(ab’)2 (Anavip®, Bioclon, Mexico) antivenom (AV) with F(ab’)2AV released in October 2018. The F(ab’)2AV Phase 3 comparative clinical trial demonstrated similar efficacy in treating venom-caused hematologic toxicity, similar rates of Types I and III hypersensitivity reactions, and a lower rate of recurrent hematological effects than FabAV. We hypothesized that a post-marketing, comparative study of effectiveness and rates of hypersensitivity reactions in treating rattlesnake envenomations in New Mexico would demonstrate similar outcomes. Patients eligible for the study presented to a New Mexico healthcare facility between May and October 2019 and were known/suspected to have a rattlesnake bite. Exclusion criteria for antivenom comparison were those with a dry bite, lost to follow-up, or late presentation. All cases were included for patient/bite demographics, initial local control, hematological control, number of maintenance/control doses, development of persistent, recurrent or late-, new-onset hematologic effects, and hypersensitivity reactions. We used Fisher's exact tests for analysis and 0.05 cutoff to determine significance. There were 54 rattlesnake-bitten patients in New Mexico with 17 excluded for comparison of antivenom because of dry bites, loss to follow-up, and one case of late presentation. Thirty-seven patients remained for comparative analysis between F(ab’)2AV (n = 11) and FabAV (n = 26). There were no significant demographic differences between F(ab’)2 and Fab-treated patients. No patient had a Type I hypersensitivity reaction. No rescue doses were given. The rate of recurrent, persistent or late-, new-onset of hematologic effects was 0% with F(ab’)2AV and 29% with FabAV. No patient was readmitted. No patient had bleeding complications. Type III hypersensitivity reactions were similar between F(ab’)2AV (36%) and FabAV (25%). The results of our study are consistent with the Phase 3 clinical comparative trial and indicate no significant differences in safety or effectiveness between FabAV and F(ab’)2AV. F(ab’)2AV offers the advantages of not requiring maintenance doses and may have a lower rate of late hematologic effects in treating rattlesnake envenomations. •Two antivenoms are available to treat rattlesnake envenomations in the United States, Fab and F(ab’)2 antivenom.•The results of our study in New Mexico are consistent with the F(ab’)2 Phase 3 comparative clinical efficacy trial.•Both Fab and F(ab’)2 antivenom showed similar rates of Type I and Type III hypersensitivity reactions.•F(ab’)2 antivenom offers the advantage of not requiring maintenance doses.•F(ab’)2 antivenom may have a lower rate of late hematologic effects in treating rattlesnake envenomations.