The aim of our study was to determine if different hypoglycemic therapies are associated with more frequent episodes of hypoglycemia in diabetes patients undergoing long-term hemodialysis. We conducted a prospective cohort study that included 102 diabetes patients who were undergoing long-term hemodialysis. The frequency of symptomatic hypoglycemic episodes, intradialytic hypotension, antihypertension medication, hypoglycemic therapy regimens, dialysate contents, and laboratory data were reviewed. The duration of follow-up was three months. Fifty-four (52.9%) patients were categorized as hypoglycemic and 48 (47.1%) patients as non-hypoglycemic. The serum albumin levels of the hypoglycemic and non-hypoglycemic patients were 3.18 +/- 0.34 g/dL and 3.44 +/- 0.33 g/dL respectively (P < 0.001). The prevalence of intradialytic hypotension is significantly higher in the hypoglycemic patients (44.4%) than in the non-hypoglycemic patients (20.8%) (P = 0.012). The risk of hypoglycemia differed significantly between the patients taking oral hypoglycemic agents (OHAs) and those receiving purely insulin therapy (P = 0.035). Multivariate analysis revealed that the serum albumin (odds ratio [OR] 0.093, 95% confidence interval [CI] 0.021-0.409), intradialytic hypotension (OR 2.755, 95% CI 1.048-7.228), and OHA therapy (OR 0.337, 95% CI 0.128-0.888) were independent factors of hypoglycemia. The patients treated only with meglitinides as hypoglycemic therapy had a significantly lower risk of hypoglycemia than those receiving mixed insulin therapy (P = 0.016). Frequent episodes of intradialytic hypotension and hypoalbuminemia are powerful clinical predictors of hypoglycemia in diabetes patients undergoing hemodialysis. It was also found that OHAs do not pose a higher risk of hypoglycemia than insulin in diabetic patients undergoing hemodialysis.