Lymphatic filariasis (LF) has been targeted for global elimination by 2020. The primary tool for the program is mass drug administration (MDA) with antifilarial medications to reduce the source of microfilariae required for mosquito transmission of the parasite. This strategy requires high MDA compliance rates. Egypt initiated a national filariasis elimination program in 2000 that targeted approximately 2.7 million persons in 181 disease-endemic localities. This study assessed factors associated with MDA compliance in year three of the Egyptian LF elimination program. 2,859 subjects were interviewed in six villages. The surveyed compliance rate for MDA in these villages was 85.3% (95% confidence interval = 83.9–86.5%). Compliance with MDA was positively associated with LF knowledge scores, male sex, and older age. Adverse events reported by 18.4% of participants were mild and more common in females. This study has provided new information on factors associated with MDA compliance during Egypt's successful LF elimination program.