Background: Both tribendimidine and mebendazole are broad-spectrum drugs for anti-intestinal nematodes. We aim to assess the efficacy and safety of tribendimidine and mebendazole in patients with co-infection of Clonorchis sinensis and other helminths. Method: We performed a randomized open-label trial in Qiyang, People's Republic of China. Eligible participants were randomly assigned to one of four groups: (i) a single dose of 400 mg tribendimidine, (ii) 200 mg tribendimidine twice daily, (iii) 75 mg/kg praziquantel divided in four doses within 2 days, and (iv) a single dose of 400 mg mebendazole. Cure rates and egg reduction rates were assessed, and adverse events were monitored after treatments. Uncured patients accepted the second treatment with the same drugs after the first treatment. Results: 156 patients were eligible for the study. Results from the first treatment showed that the cure rates of single-dose tribendimidine and praziquantel against C. sinensis were 50% and 56.8%, respectively; the single-dose tribendimidine achieved the cure rate of 77.8% in the treatment for hookworm, which was significantly higher than that of praziquantel; Low cure rates were obtained in the treatment of single-dose tribendimidine against Ascaris lumbricoides and Trichuris trichiura (28.6% and 23.1%). Results of the second treatment illustrated the cure rates of tribendimidine and praziquantel against C. sinensis were 78.1% and 75%, respectively. Most adverse events were mild and transient. Adverse events caused by tribendimidine were significantly less than praziquantel. Conclusion: Single-dose tribendimidine showed similar efficacy against C. sinensis as praziquantel with less adverse events, and achieved significantly higher cure rate in the treatment for hookworm than those of praziquantel and mebendazole. Low cure rates, which were still higher than other drugs, were obtained in the treatment of single-dose tribendimidine against Ascaris lumbricoides and Trichuris trichiura. Trial Registration: Controlled-Trials.com ISRCTN55086560 Author Summary: Co-infection of Clonorchis sinensis and other helminths is common in places with poor settings. Preventive chemotherapy is commonly used to control the co-infection of helminths due to lack of effective vaccine. It is important to investigate the efficacy and safety of tribendimidine, a broad-spectrum anti-intestinal nematodes drug, against co-infection of C. sinensis and other helminths, in comparison with those of praziquantel and mebendazole. The cure rates of single-dose 400 mg tribendimidine against C. sinensis, hookworm, Ascaris lumbricoides and Trichuris trichiura in this study were 50%, 77.8%,28.6% and 23.1%, respectively. The single-dose tribendimidine achieved similar efficacy as the four-dose praziquantel in the treatment for C. sinensis with significantly less adverse events. Meanwhile, significantly higher cure rate of tribendimidine was found in the treatment for hookworm than other drugs. Most adverse events were mild and transient in this study. Tribendimidine seems a better drug choice for the patients co-infected with C. sinensis and other helminths than that of praziquantel. [ABSTRACT FROM AUTHOR]