Burmese pythons (Python bivittatus Kuhl, 1820) are one of the world’s largest snake species, making them a highly successful and biologically damaging invasive predator in the Greater Everglades Ecosystem, Florida, USA. Though we have knowledge of python diet within this system, we understand very little of other interactions with native species. Effects native species have on invasive pythons, especially in the juvenile size class, are of particular interest as the prevalence of mortalities would inform potential population growth and trophic dynamics with native prey species. Native ophiophagous predators in Florida feed on smaller native snake species and it is unknown if they consistently recognize similarly sized juvenile invasive pythons as prey items. Using radiotelemetry, we found at least four native species within Big Cypress National Preserve that were implicated in juvenile python deaths, including three Florida cottonmouths (Agkistrodon conanti Gloyd, 1969), five American alligators (Alligator mississippiensis Daudin, 1802), one hispid cotton rat (Sigmodon hispidus Say and Ord, 1825), and three mesomammals. One mortality was the result of an attempt to subdue a prey item 106% the size of the python, constituting the largest predator:prey size ratio ever reported in this size class. This finding may indicate that phenotypic variation in individual juvenile pythons includes behavior that could be maladaptive within the novel Florida environment. Here we describe some of the first confirmed cases of non-anthropogenic mortality in juvenile Burmese pythons in Florida and present evidence that invasive pythons in this size class are now being incorporated into the diets of native species in its invasive range Burmese pythons (Python bivittatus Kuhl, 1820) are one of the world’s largest snake species, making them a highly successful and biologically damaging invasive predator in the Greater Everglades Ecosystem, Florida, USA. Though we have knowledge of python diet within this system, we understand very little of other interactions with native species. Effects native species have on invasive pythons, especially in the juvenile size class, are of particular interest as the prevalence of mortalities would inform potential population growth and trophic dynamics with native prey species. Native ophiophagous predators in Florida feed on smaller native snake species and it is unknown if they consistently recognize similarly sized juvenile invasive pythons as prey items. Using radiotelemetry, we found at least four native species within Big Cypress National Preserve that were implicated in juvenile python deaths, including three Florida cottonmouths (Agkistrodon conanti Gloyd, 1969), five American alligators (Alligator mississippiensis Daudin, 1802), one hispid cotton rat (Sigmodon hispidus Say and Ord, 1825), and three mesomammals. One mortality was the result of an attempt to subdue a prey item 106% the size of the python, constituting the largest predator:prey size ratio ever reported in this size class. This finding may indicate that phenotypic variation in individual juvenile pythons includes behavior that could be maladaptive within the novel Florida environment. Here we describe some of the first confirmed cases of non-anthropogenic mortality in juvenile Burmese pythons in Florida and present evidence that invasive pythons in this size class are now being incorporated into the diets of native species in its invasive range.