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Introduction There is some evidence that homeopathic treatment has been used successfully in previous epidemics, and currently some countries are testing homeoprophylaxis for the coronavirus disease 2019 (COVID-19) pandemic. There is a strong tradition of homeopathic treatment in India: therefore, we decided to compare three different homeopathic medicines against placebo in prevention of COVID-19 infections. Methods In this double-blind, cluster-randomized, placebo-controlled, four parallel arms, community-based, clinical trial, a 20,000-person sample of the population residing in Ward Number 57 of the Tangra area, Kolkata, was randomized in a 1:1:1:1 ratio of clusters to receive one of three homeopathic medicines (Bryonia alba 30cH, Gelsemium sempervirens 30cH, Phosphorus 30cH) or identical-looking placebo, for 3 (children) or 6 (adults) days. All the participants, who were aged 5 to 75 years, received ascorbic acid (vitamin C) tablets of 500 mg, once per day for 6 days. In addition, instructions on healthy diet and general hygienic measures, including hand washing, social distancing and proper use of mask and gloves, were given to all the participants. Results No new confirmed COVID-19 cases were diagnosed in the target population during the follow-up timeframe of 1 month—December 20, 2020 to January 19, 2021—thus making the trial inconclusive. The Phosphorus group had the least exposure to COVID-19 compared with the other groups. In comparison with placebo, the occurrence of unconfirmed COVID-19 cases was significantly less in the Phosphorus group (week 1: odds ratio [OR], 0.1; 95% confidence interval [CI], 0.06 to 0.16; week 2: OR, 0.004; 95% CI, 0.0002 to 0.06; week 3: OR, 0.007; 95% CI, 0.0004 to 0.11; week 4: OR, 0.009; 95% CI, 0.0006 to 0.14), but not in the Bryonia or Gelsemium groups. Conclusion Overall, the trial was inconclusive. The possible effect exerted by Phosphorus necessitates further investigation. Trial registration: CTRI/2020/11/029265.