Disease‐induced variations of plasma albumin (ALB) and alph1‐acid glycoprotein (AAG) levels were investigated in dogs. Lower ALB (sometimes >50% reduction) and higher AAG (sometimes >10‐fold increase) levels were observed in dogs with various diseases. Drug binding was determined at therapeutic concentrations using normal, low‐ALB and high‐AAG dog plasma. The binding percentages of the ALB‐binding drugs decreased in low‐ALB plasma, resulting in a large increase in unbound drug, particularly for naproxen (a 13‐fold increase). The binding percentages of all AAG‐binding drugs investigated in this study increased in high‐AAG plasma, resulting in a large decrease in unbound drug, particularly for quinidine (99% decrease). The fluctuation in the unbound fraction of drugs could affect their efficacy or could cause side‐effects. Veterinary clinicians should monitor the ALB and AAG levels in the plasma of patients and correct dosage regimens according to these levels, where field conditions permit this, in order to ensure the proper usage of drugs with high affinity for ALB or AAG.