Controlling blood glucose levels is the main target in pregnant women with gestational diabetes mellitus (GDM). Twin pregnancies are offered the same screening selection and have the same diagnostic criteria as well as treatment of gestational diabetes as singleton pregnancies, even though the risks for pregnancy complications are increased. The aim of this study was to assess the association between predicting factors, OGTT glucose levels and pharmacotherapy requirements in twin pregnancies with GDM. This retrospective cohort study included 446 GDM patients with twin pregnancies (246 managed with lifestyle modifications and 200 requiring pharmacotherapy) over a time period of 18 years. An evaluation of maternal characteristics and a standardized 75 g oral glucose test (OGGT) for glucose concentrations at fasting, 1 h and 2 h were conduced. OGTT glucose levels at fasting (=0 min, p < 0.01) and 1 h (p < 0.01) were significantly associated with the later requirement of pharmacotherapy. Also, clinical risk factors (pre-pregnancy BMI p < 0.01, multiparity p < 0.05, GDM in previous pregnancy p < 0.01, assisted reproduction p < 0.05) showed a predictive accuracy for insulin therapy in twin pregnancies complicated by GDM, whereas age and chorionicity had no effect. OGTT glucose measures in addition to clinical risk factors are promising variables for risk stratification in mothers with GDM and twin pregnancy.