A comparative pharmacokinetic study of diclofenac (1 mg/kg, i.v.) when given alone or in combination with enrofloxacin (4 mg/kg, i.v.) in five buffalo calves was carried out by using HPLC. The study revealed that the plasma concentrations of diclofenac were significantly lower (p<0.05) in combined administration of diclofenac with enrofloxacin (0.042 to 3 h), whereas significantly higher (p<0.05) levels of plasma drug concentrations were observed in later period (8 to 24 h). In urine, significantly lower (p<0.05) drug concentrations of diclofenac were observed from 0.167 to 1.5 h, whereas significantly higher (p<0.01) urine drug concentrations were observed in later period (4 to 48 h) when diclofenac was given in combination with enrofloxacin as compared to when diclofenac was given alone. Various kinetic parameters like A, Cpo and beta were significantly lower (p<0.05) whereas t1/2 beta, AUMC, MRT and various volume of distribution (VdC, VdB, Vdarea and VdSS) were significantly higher in combined administration of diclofenac with enrofloxacin as compared to when diclofenac was given alone (p<0.05).