Diabetes mellitus (DM) is a risk factor for complication in influenza infection. Annual influenza vaccination is considered the best strategy for protection. Type I interferons (IFNs) are important for host defense against viral infection by enhancing antiviral functions of adaptive immune cells and antibodies. Mostly, DM individuals in Thailand and other low-middle income countries are prescribed metformin and/or glibenclamide to control blood glucose level. However, the persistency and magnitude of antibody and type I IFN responses induced by seasonal trivalent influenza vaccine (TIV) and the effect of anti-diabetic treatment are unclear. Here we determined the antibody responses against seasonal TIV by HAI and ELISA in DM versus non-DM at the baseline (Day -7) and Day 30, 90 and 270 post-vaccination. IFN-α gene expression in whole blood in response to TIV was quantified by real time PCR. We found that seasonal TIV elicited sero-protection (HAI titer >40) by Day 30 post-vaccination persisting for at least 90 days and declined by Day 270 in both DM and non-DM groups. However, DM individuals showed lower sero-response (HAI titer fold rise >4) and less persistency of antibody in response to influenza type B antigen. Interestingly, the reduced IgG antibody to influenza antigens and affinity antibody fold change were correlated with the time duration of anti-diabetic treatment. Moreover, we found the reduced IFN-α gene expression in response to seasonal TIV in DM who had been treated with metformin to control blood glucose whilst no differences in HbA1c level. Taken together, these results suggest that prolong anti-diabetic treatment could affect IFN-α gene expression and influenza vaccine induced antibody response. The information may be useful to improve vaccine efficacy for DM individuals.