OBJECTIVES:  Patients’ adherence to antihyperglycemic medication is an essential component in achieving adequate glycemic control. Non-adherence can lead to macro vascular and micro vascular complications among patients with type 2 diabetes mellitus (T2DM). According to SAMSHA’s opioid use guideline, prescription opioid use can negatively impact chronic asymptomatic medication therapy. Thus, antihyperglycemic medication adherence may decrease and subsequently lead to T2DM related hospitalizations. METHODS:  This was a retrospective cohort analysis using 2003-2004 Truven MarketScan_® commercial claims databases. T2DM patients greater than 18 years who were prescribed prescription opioids were included. Adherence to antihyperglycemic medications was calculated among long-term (≥ 90 days) opioid users and short-term (< 90 days) opioid users. Medication adherence (PDC) was estimated with PDC ≥0.80 considered adherent. Subsequent T2DM related hospitalizations was estimated using a cox proportional hazard regression model, comparing long-term and short-term prescription opioid users. RESULTS:  After inclusion criteria was applied, data on 22,212 patients were observed, out of which 7,462 (33.66%) were long-term opioid users. During the 6-month follow-up, risk of T2DM related hospitalization was lower among long-term opioid users with150 days or less during follow-up (HR = 0.73, 95% CI = 0.69-0.78) as compared to short-term prescription opioid users. Risk of T2DM related hospitalization was higher among patients with long-term prescription opioid use greater than150 days during the follow-up (HR = 1.25, 95% CI = 0.69- 2.28) as compared to short-term opioid users. Follow-up antihyperglycemic adherence (HR = 1.44, 95% CI = 1.25-1.64) was a significant predictor of T2DM related hospitalization when assessed as a mediator. CONCLUSIONS:  Patients who were concomitantly prescribed long-term prescription opioids and antihyperglycemic medications were at a lower risk of T2DM related hospitalizations as compared to patients who were prescribed short-term prescription opioids. Use of prescription opioids over a longer duration did not negatively impact T2DM related hospitalizations when prescribed concomitantly in this study.