Abstract Objectives We aimed to investigate the relationship between serum paraoxonase-1 (PON1) and paraoxonase-3 (PON3) levels and activities with hemoglobin A1c (HbA1c), serum fasting blood glucose, lipid profile, and oxidative stress in patients with type 2 diabetes mellitus (T2DM). Also, we aimed to examine PON1 and PON3 levels and activities in these patients according to the HbA1c goal in diabetes treatment and PON1192 phenotypes. Methods One hundred forty-one volunteers diagnosed with T2DM participated in this study. Serum PON1 and PON3 levels and activities, total oxidant status (TOS), and total antioxidant status (TAS) were measured. PON1192 phenotypes were determined by using PON1 activities. Also, HbA1c, serum fasting blood glucose, and lipid profile results, which were measured for routine examination on the same day as sample collection, were used for this study. Results There was a positive relationship between arylesterase and lactonase activities and high-density lipoprotein cholesterol (HDL-C), between lactonase activity and TAS, and a negative relationship between PON1 level and TAS in patients with T2DM. Our study also showed that PON3/HDL-C was higher in patients with HbA1c levels ≥7 %. Lactonase activities were higher in patients with PON1Q192Q and PON1Q192R phenotypes than in patients with PON1R192R phenotypes. Conclusions PON1 and PON3 levels and activities alone could not be associated with immediate or long-term blood glucose levels in patients with T2DM. Higher PON3/HDL-C in patients with HbA1c levels ≥7 % may show a protective role of PON3 in defense against higher glucose levels. Also, we found that the PON1192 phenotype can affect serum lactonase activity.