Discharges from pharmaceutical manufacturing facilities (PMFs) previously have been identified as important sources of pharmaceuticals to the environment. Yet few studies are available to establish the influence of PMFs to the pharmaceutical source contribution to wastewater treatment plants (WWTPs) and waterways at the national scale. Consequently, a national network of 13 WWTPs receiving PMF discharges and 7 WWTPs with no PMF input (controls) were selected from across the United States to assess the influence of PMF input for a diverse suite of pharmaceuticals being formulated for a range of WWTP sizes. WWTP effluent samples were collected and analyzed for 120 pharmaceuticals and pharmaceutical degradates. Of these, 33 pharmaceuticals had concentrations significantly higher in PMF-influenced effluent (maximum 555,000 nanograms per liter) compared to effluent from control sites (maximum 175 nanograms per liter). Concentrations in PMF discharges are episodic and indicate that production activities can vary substantially over relatively short (several months) periods and the potential to rapidly transition to other pharmaceutical products. Results show that PMFs are an important, national-scale source of pharmaceuticals to the environment. Additional research is needed to determine if the observed elevated pharmaceutical concentrations discharged from PMF-influenced WWTPs translate to an increase in adverse environmental effects in corresponding waterways.