To assess the performance of an educational campaign to increase adherence to a mass-administered DEC regimen against lymphatic filariasis (LF) in Orissa, and to identify factors that could enhance future campaigns. Randomized cluster survey, comparing areas that did and did not receive the educational campaign, using a household coverage survey and knowledge, attitudes and practices (KAP) survey. LF MDA coverage for the entire population (n = 3449) was 56% (95% CI: 50.0-61.9). There was no statistical difference between the areas that did and did not receive the educational campaign. The most common barriers to adherence were fear of medication side effects (47.4%) and lack of recognition of one's risk for LF (15.8%). Modifiable, statistically significant, multivariable predictors of adherence were knowing that DEC prevents LF (aOR = 2.6, 95% CI: 1.4-5.1), knowing that mosquitoes transmit LF (aOR = 1.9, 95% CI: 1.1-3.2), and knowing both about the mass drug administration (MDA) in advance and that mosquitoes transmit LF (aOR = 5.4, 95% CI: 2.8-10.4). India needs to increase compliance with MDA programmes to reach its goal of interrupting LF transmission. Promoting a simple public health message before MDA distribution, which takes into account barriers to and predictors of adherence, could raise compliance with the LF MDA programme.