Shrimp are among the most highly valued seafood in the US, and a large proportion are cultured. At least seven species of Vibrio bacteria and other pathogens often infect shrimp during some stage of culture, having profound impacts on productivity. The research described herein was conducted to optimize dosing to allow effective disease control while minimizing environmental residues. Pharmacokinetics of oxytetracycline (OTC), a broad spectrum antibiotic were evaluated in the white shrimp, Litopenaeus setiferus, to characterize its disposition and to determine its potential for use in farm-raised shrimp for the treatment of Vibrio infections. Intravascular dosing and sampling techniques were developed, since this was the first pharmacokinetic study in shrimp using survival sampling. Pharmacokinetics of OTC were evaluated after single low and high bolus intravascular doses and hemolymph sampling. Tissue distribution was investigated after systemic administration, and protein binding was studied in hemolymph isolated from shrimp using ultrafiltration. The hemolymph and tissue levels of OTC were measured by HPLC and fitted to appropriate pharmacokinetic models to characterize the disposition of OTC in shrimp. Hemolymph OTC concentration–time profiles were well described by a biexponential equation indicative of two-compartment pharmacokinetics of OTC in shrimp. The half-lives of distribution and elimination were 2.05±0.48 and 22.27±7.45 h, respectively. Systemic clearance and steady-state volume of distribution were 78.04±24.33 ml/h/kg and 2304±280 ml/kg, respectively. OTC levels in tail muscle (% of total body burden) were significantly lower than in hemolymph, minimizing concerns of OTC residue in edible shrimp tissue after OTC treatment. Hemolymph protein binding of OTC was found to be low with almost 80% free OTC available systemically, supporting the high volume of distribution observed. Despite the simple anatomy, small size and short life span of shrimp, the disposition of OTC in shrimp after intravascular dosing showed pharmacokinetic characteristics indicative of extensive tissue distribution, such as a long elimination half-life and a high volume of distribution, with the low potential for OTC residues in tail muscle tissue. Our results suggest that shrimp given a therapeutic dose of OTC (i.e., sufficient to exceed the MIC) will have no detectable OTC levels in edible tissues 14 days following withdrawal. However, the salt form and formulation of OTC in feeds can impact dissolution, bioavailability, pharmacokinetics and, hence, tissue residues. Thus, withdrawal times should not be drug or agent specific but product and formulation specific. These results must be confirmed with oral dosing studies and bioavailability determinations that are underway in our laboratory.