Aims: The aim was to evaluate the impact of family history of diabetes on the phenotype of patients diagnosed with Type 2 diabetes and the frequency of susceptibility genotypes. Methods: Patients with Type 2 diabetes with family history for both Type 1 and Type 2 diabetes (FH_MIX, n = 196) or Type 2 diabetes only (FH_T2, n = 139) matched for age, sex, BMI and age at diagnosis, underwent an oral glucose tolerance test and a combined glucagon test and insulin tolerance test. Glutamic acid decarboxylase (GAD) antibodies and major Type 1 and Type 2 diabetes susceptibility gene variants were analysed. Patients were stratified into groups according to family history or GAD antibody positivity (GADA+, GADA-) or a combination of these (GADA+/FH_MIX, GADA+/FH_T2, GADA-/FH_MIX, GADA-/FH_T2). Results: Compared with other patients, those with FH_MIX more often had GAD antibodies (14.3 vs. 4.3%, P = 0.003), and those with both FH_MIX and GAD antibodies had the highest frequency of insulin deficiency (stimulated serum C-peptide < 0.7 nmol/l, GADA+/FH_MIX 46.4% vs. GADA-/FH_MIX 9.5% (P < 0.00001), GADA-/FH_T2 4.5% (P < 0.00001), GADA+/FH_T2 0%). Patients with GADA+/FH_MIX more often had HLA-DQB1 risk genotypes compared with patients with GADA-/FH_MIX or GADA-/FH_T2D (47 vs. 23 or 14%, P = 0.05 and P < 0.00001, respectively). In logistic regression analyses, FH_MIX, GAD antibody positivity and HLA risk genotypes were independently associated with insulin deficiency. Conclusion: A family history for both type 1 and type 2 diabetes was associated with higher prevalence of GAD antibodies and HLA-DQB1 risk genotypes than a family history of type 2 diabetes only, and was associated with earlier and more severe development of insulin deficiency, which was only partially explained by GAD antibodies and HLA.