The potential impact on human health from antibiotic-resistant bacteria selected by use of antibiotics in food animals has resulted in many reports and recommended actions. The U.S. Food and Drug Administration Center for Veterinary Medicine has issued Guidance Document 152, which advises veterinary drug sponsors of one potential process for conducting a qualitative risk assessment of drug use in food animals. Using this guideline, we developed a deterministic model to assess the risk from two macrolide antibiotics, tylosin and tilmicosin. The scope of modeling included all label claim uses of both macrolides in poultry, swine, and beef cattle. The Guidance Document was followed to define the hazard, which is illness (i) caused by foodborne bacteria with a resistance determinant, (ii) attributed to a specified animal-derived meat commodity, and (iii) treated with a human use drug of the same class. Risk was defined as the probability of this hazard combined with the consequence of treatment failure due to resistant Campylobacter spp. or Enterococcus faecium. A binomial event model was applied to estimate the annual risk for the U.S. general population. Parameters were derived from industry drug use surveys, scientific literature, medical guidelines, and government documents. This unique farm-to-patient risk assessment demonstrated that use of tylosin and tilmicosin in food animals presents a very low risk of human treatment failure, with an approximate annual probability of less than 1 in 10 million Campylobacter-derived and approximately 1 in 3 billion E. faecium-derived risk.