Background Guyana is one of four countries in the Latin American Region where lymphatic filariasis (LF) remains endemic. In preparation for the introduction of a new triple drug therapy regimen (ivermectin, diethylcarbamazine, and albendazole (IDA)) in 2019, an acceptability study was embedded within sentinel site mapping in four regions to assess mass drug administration (MDA) coverage and compliance, acceptability, and perceptions about treatment and disease. The results from this survey would inform the rollout of IDA in Guyana in 2019. Methods Data collection for the study occurred in August 2019, using a validated questionnaire administered by trained enumerators. Across all regions, a total of 1,248 participants were sampled by the Filarial Mapping team. Four-hundred and fifty-one participants aged over 18 years were randomly selected for participation in an expanded acceptability questionnaire. All data were captured in Secure Data Kit (SDK). Results Acceptability was measured using a mean acceptability score. Unadjusted mean scores ranged from 24.6 to 29.3, with 22.5 as the threshold of acceptability. Regional variation occurred across many indicators of interest: self-rated understanding about LF, mechanisms of LF transmission, LF drug safety and history of treatment during MDA. Region IV (Georgetown) recorded higher knowledge about LF, but lower compliance and acceptability. Number of pills was not perceived as a concern. Conclusion Acceptability of MDA was good across all four regions under study. Results from this study set a baseline level for key indicators and acceptability, from which the acceptability of IDA can be measured. Regional variations across indicators suggest that localized approaches should be considered for social mobilization and MDA delivery to capture these contextual differences.