Interest in the risks posed by trace concentrations of pharmaceuticals and personal care products (PPCPs) in surface waters is increasing, particularly with regard to potential effects of long-term, low-dose exposures of aquatic organisms. In most cases, the actual studies on PPCPs were risk assessments at screening-level, and accurate estimates were scarce. In this study, exposure and ecotoxicity data of 50 PPCPs were collected based on our previous studies, and a multiple-level environmental risk assessment was performed. The 50 selected PPCPs are likely to be frequently detected in surface waters of China, with concentrations ranging from the ng L to the low-g L, and the risk quotients based on median concentrations ranged from 2046 for nonylphenol to 0 for phantolide. A semi-probabilistic approach screened 33 PPCPs that posed potential risks to aquatic organisms, among which 15 chemicals (nonylphenol, sulfamethoxazole, di (2-ethylhexyl) phthalate, 17β-ethynyl estradiol, caffeine, tetracycline, 17β-estradiol, estrone, dibutyl phthalate, ibuprofen, carbamazepine, tonalide, galaxolide, triclosan, and bisphenol A) were categorized as priority compounds according to an optimized risk assessment, and then the refined probabilistic risk assessment indicated 12 of them posed low to high risk to aquatic ecosystem, with the maximum risk products ranged from 1.54% to 17.38%. Based on these results, we propose that the optimized risk assessment was appropriate for screening priority contaminants at national scale, and when a more accurate estimation is required, the refined probability risk assessment is useful. The methodology and process might provide reference for other research of chemical evaluation and management for rivers, lakes, and sea waters.