The waterway also contains pathogens that cause tuberculosis, encephalitis, polio, cholera, hepatitis and typhoid; levels for many of these contaminants violate United States Environmental Protection Agency (EPA) and Cal/EPA standards by several hundredfold.

[7] Highly polluted inflow to the New River and agricultural runoff has resulted in elevated bacterial levels and large algal blooms in the Salton Sea.

Some water still flowed after the dyke was repaired, as the larger channels collected and carried agricultural runoff to the Salton Sea.

Studies in 1947 and 1948 of the New River led the IBWC to recommend a joint treatment plant constructed in the United States to treat the sewage from Calexico and Mexicali.

Due to inadequate sewer infrastructure, the two nations attempted in the 1980s and 1990s to address pollution in this river, as documented by the International Boundary and Water Commission of the U.S. Department of State.

Once viewed as a model of international cooperation, in recent decades, the IBWC has been heavily criticized as an institutional anachronism, bypassed by modern social, environmental, and political issues.

The EPA paid 55% of a $50 million upgrade to Mexicali's sewage treatment facilities, but the improvements did not treat all waste discharges into the river.

The New River is so heavily polluted that technicians usually wear two sets of gloves, aprons, and other protective clothing when testing the water.

[13] Discarded trash, dead animals and other waste line the channel, whose foam blows into the streets of a Calexico residential area and its downtown.

[14] The California Office of Environmental Health Hazard Assessment has issued a safe eating advisory for any fish caught in New River due to elevated levels of mercury, DDTs, PCBs, and selenium.

While this should result in measurably improved water quality of the New River at the border, particularly as it relates to pathogens and nutrients, the binational projects do not address the dumping of trash into the New River and its tributaries, the nutrients and pathogens from Mexicali's Zaragoza wastewater treatment lagoons, the untreated and partially treated discharges of industrial wastes, agricultural runoff from the Mexicali Valley, and urban and storm runoff from the municipality.

Mexico intends to reclaim effluent from the treatment plant for onsite green belts, resulting in a 20 million US gallons (76,000 m3) per day decrease in the flow of the New River at the border, in addition to the projected 10 million US gallons (38,000 m3) per day decrease in flow in the river at the border when the InterGen and Sempra Energy power plants reach capacity in Mexicali.

Agricultural pesticides have never been detected in the Salton Sea at levels high enough to cause a public health concern.