A biologically based risk-assessment model of arsenic (As) exposure evaluated farmed tilapia (Orechromis mossambicus) and human health during tilapia consumption in an area of southwestern Taiwan where blackfoot disease (BFD) occurs. The risk assessment addressed exposures to city residents who lived in Taipei, Taichung, and Kaohsiung, as well as subsistence fishers living in the BFD area who consumed tilapia. The models implemented included a physiologically based toxicokinetic and toxicodynamic (PBTK/TD) model to account for As exposure and dose-response profiles in tilapia and a human health exposure/risk model that accounts for target lifetime risk (TR) and hazard quotient (HQ) for humans consuming farmed tilapia. Results demonstrated that 90th percentiles of TR ranged from 1.53 × 10−8 to 1.62 × 10−6 for city residents with farmed tilapia consumption rates of 0.41 to 1.37 g/d. The 90th percentiles ranged from 2.07 ×10−6 to 7.89 ×10−5 for subsistence fishers in the BFD area with farmed tilapia consumption rates of 16.80 to 59.15 g/d. All predicted 90th percentiles of HQ were less than 1 for city residents and subsistence fishers in the BFD area, indicating small contributions from farmed tilapia consumption. Critical variables included whole-fish body weight, water As content, and As level in tilapia muscle. Although bioaccumulation of As seems unlikely to result in toxicity to farmed tilapia and humans consuming tilapia, the theoretical human health risks in the BFD area are alarming, using a probabilistic risk-assessment model based on conservative assumptions.