Preventive chemotherapy with diethylcarbamazine citrate (DEC) and albendazole (ALB) is the core intervention strategy to eliminate lymphatic filariasis (LF). We conducted a large‐scale prospective active safety surveillance study to identify the incidence, type, severity, and risk factors for adverse events (AEs) following mass drug administration (MDA) of single‐dose DEC and ALB in 10,010 participants from Kilifi County, Kenya. AEs were actively monitored and graded at 24 h, 48 h, and on day 7 Post‐MDA. Out of 10,010 enrolled study participants, 1621 participants reported a total of 3102 AEs during a seven‐day follow‐up. The cumulative incidence of AEs was 16.2% (95% CI, 15.5–16.9%). The proportion of participants who experienced one, two, or ≥ three types of AEs was 9.2%, 4.6%, 2.4%, respectively. AEs were mild (87.3%), moderate (12.4%), and severe (0.3%) and resolved within 72 h. The five most common AEs were dizziness (5.9%), headache (5.6%), loss of appetite (3.3%), fever (2.9%), and drowsiness (2.6%). Older age, taking concurrent medications, ≥ three tablets of DEC, and type of meal taken before MDA were significant predictors of AEs. One in six participants experienced systemic mild‐to‐moderate severity grading and transient AEs. DEC and ALB co‐administration for the elimination of LF is generally safe and well‐tolerated.
