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Spatial and temporal variations have been found in the levels of arsenic (As) throughout the groundwater of the Ghaghara basin. Fifteen out of twenty-five districts in this basin are reported to be affected by As, where the levels of As in groundwater and soil exceed the permissible limits set by the WHO (10 μgl−1) and FAO (20 mgkg−1) respectively. These districts include a total of four municipalities in Nepal and eighty-six blocks in India, all of which have varying degrees of As contamination. Approximately 17 million people are at risk of As poisoning, with more than two orders of magnitude higher potential lifetime incremental cancer risk, constituting over 153 thousand potential additional cases of cancer due to As-contaminated drinking water. Out of the 90 As-contaminated blocks in the Ghaghara basin, 4 blocks have about 7-fold higher potential risk of developing cancer, 49 blocks have 8–37-fold higher risk, and 37 blocks have up to 375-fold higher risk compared to the upper limit of the USEPA acceptable range, which is 1 × 10−6-1 × 10−4. High accumulation of As has been reported in the nails, hair, and urine of local inhabitants, with higher levels observed in females than males. The toxicity of As is manifested in terms of a higher occurrence of various diseases. Reproductive endpoints, such as increased incidences of preterm birth, spontaneous abortion, stillbirth, low-birth weight, and neonatal death, have also been reported in the basin. The level of As in tube wells has been found to be negatively correlated with the depth (r = −0.906), and tube wells with high levels of As (>150 μgl−1) are generally located within close proximity (<10 km) to abandoned or present meander channels in the floodplain areas of the Ghaghara river. In addition to As contamination, the water quality index (WQI) in the Ghaghara basin is poor according to the BIS standards for drinking water. Groundwater in six out of fifteen districts is unsuitable for drinking purposes, with a WQI exceeding 100. The levels of As in agricultural soil in many villages of Ballia, Bahraich, and Lakhimpur Kheri districts have exceeded the FAO limit. Water from deep tube wells has been found to be relatively safe in terms of As content, and thus can be recommended for drinking purposes. However, the use of surface water needs to be encouraged for irrigation purposes in order to preserve soil health and reduce As contamination in the food chain, thereby minimizing the risk of cancer. [Display omitted] • More than 17 million people are at risk of arsenic poisoning in the Ghaghara basin. • Potential cancer risk is more than two orders of magnitude higher than USEPA limit. • Arsenic accumulation is higher in hair and nails of female compared to males. • Area within 10 km distance from midstream of Ghaghara river is most contaminated. • Groundwater arsenic levels and depth of tube wells are inversely related. [ABSTRACT FROM AUTHOR]