Background: Podoconiosis is an underreported lymphoedema whose distribution is uncertain at global level and within endemic countries. Previous work has identified countries with historical evidence of podoconiosis, but which do not currently report cases. Podoconiosis may persist in these countries or have been eliminated due to socioeconomic development. Here we describe two different approaches used to clarify podoconiosis endemicity status in Guatemala and in Idukki District (Kerala State, India). Methods: Two different epidemiological approaches were used by different research teams, determined by the available resources and contextual factors in the two settings. In Guatemala, where lymphoedema cases are routinely recorded in the health information system, 102 municipalities with suspected cases, historical evidence of podoconiosis, high poverty rates, or environmental suitability for the disease were visited. Active case searches were conducted from July 2016 to October 2018, and suspected cases were clinically examined to confirm or rule out podoconiosis. In Idukki, where lymphoedema cases were not routinely recorded, a population-based prevalence survey for lymphoedema was conducted from September to December 2022, covering 13,664 individuals aged 15 years and older. Results: Both approaches were effective at clarifying podoconiosis endemicity. In Guatemala, 20 cases with lower limb swelling were investigated. Podoconiosis was ruled out in all cases, and filarial lymphoedema was suspected in three. In Idukki District, 105 cases of lower limb swelling were identified. None was confirmed to have podoconiosis, with post-surgical lymphoedema and hypertension being the most common diagnoses. Active filarial infection was identified in two cases in Idukki District. Conclusions: These investigations provide evidence that podoconiosis is currently non-endemic in Guatemala and in Idukki District in India. They also demonstrate that population-based surveys and targeted case searches both provide effective ways to explore disease endemicity in areas where this is uncertain. The most appropriate approach depends on a combination of contextual and research-based factors, including evidence for endemicity, resources available, and geographical, population, and health system factors.