Background Papua New Guinea (PNG) has a high burden of lymphatic filariasis (LF) caused by Wucher-eria bancrofti, with an estimated 4.2 million people at risk of infection. A single co-adminis-tered dose of ivermectin, diethylcarbamazine and albendazole (IDA) has been shown to have superior efficacy in sustained clearance of microfilariae compared to diethylcarbama-zine and albendazole (DA) in small clinical trials. A community-based cluster-randomised trial of DA versus IDA was conducted to compare the safety and efficacy of IDA and DA for LF in a moderately endemic, treatment-naive area in PNG. Methodology All consenting, eligible residents of 24 villages in Bogia district, Madang Province, PNG were enrolled, screened for W. bancrofti antigenemia and microfilaria (Mf) and randomised to receive IDA (N = 2382) or DA (N = 2181) according to their village of residence. Adverse events (AE) were assessed by active follow-up for 2 days and passive follow-up for an addi-tional 5 days. Antigen-positive participants were re-tested one year after MDA to assess treatment efficacy. Principal findings Of the 4,563 participants enrolled, 96% were assessed for AEs within 2 days after treat-ment. The overall frequency of AEs were similar after either DA (18%) or IDA (20%) treat-ment. For those individuals with AEs, 87% were mild (Grade 1), 13% were moderate (Grade 2) and there were no Grade 3, Grade 4, or serious AEs (SAEs). The frequency of AEs was greater in Mf-positive than Mf-negative individuals receiving IDA (39% vs 20% p<0.001) and in Mf-positive participants treated with IDA (39%), compared to those treated with DA (24%, p = 0.023). One year after treatment, 64% (645/1013) of participants who were antigen-positive at baseline were re-screened and 74% of these participants (475/ 645) remained antigen positive. Clearance of Mf was achieved in 96% (52/54) of infected individuals in the IDA arm versus 84% (56/67) of infected individuals in the DA arm (rela-tive risk (RR) 1.15; 95% CI, 1.02 to 1.30; p = 0.019). Participants receiving DA treatment had a 4-fold higher likelihood of failing to clear Mf (RR 4.67 (95% CI: 1.05 to 20.67; p = 0.043). In the DA arm, a significant predictor of failure to clear was baseline Mf density (RR 1.54; 95% CI, 1.09 to 2.88; p = 0.007). Conclusion IDA was well tolerated and more effective than DA for clearing Mf. Widespread use of this regimen could accelerate LF elimination in PNG. Trial registration Registration number NCT02899936; https://clinicaltrials.gov/ct2/show/NCT02899936.