OBJECTIVES: Prandial insulins are a key component in insulin treatment in type 1 diabetes mellitus (T1DM) and many type 2 diabetes mellitus (T2DM) patients. The evidence supporting a choice between available insulin preparations is still limited. We performed a systematic review of clinical data comparing efficacy and safety of insulin aspart (IAsp) and regular human insulin (RHI) in both types of diabetes. METHODS: Randomized controlled trials (RCTs) directly comparing IAsp with RHI after ≥12 weeks of treatment in patients with either T1DM or T2DM receiving prandial insulin regimens were retrieved within systematic search of medical databases (MEDLINE, EMBASE, Cochrane’s CENTRAL) carried out up to May 2013. Results from individual studies were meta-analyzed and presented as weighted mean difference (WMD) or relative risk (RR). RESULTS: Of 16 RCTs considered relevant for the current review, 11 papers referred to T1DM and 5 were representative for T2DM patients. Pooled results for T1DM population demonstrated that IAsp as compared with RHI provided larger reduction of the HbA1c level (9 RCTs; WMD[95%CI]=-0.11% [-0.16, -0.05]) as well as better postprandial glucose level following breakfast (4 RCTs; WMD[95%CI]=-1.40mmol/L [-1.72, -1.07]), lunch (3 RCTs; WMD[95%CI]=-1.01mmol/L [-1.61, -0.41]) and dinner (4 RCTs; WMD[95%CI]=‑0.89mmol/L [-1.19, -0.59]). The risk of nocturnal hypoglycemia was lower in T1DM patients treated with IAsp (4 RCTs; RR=0.76 [0.64, 0.91]), while no difference was observed for severe hypoglycemic events. In T2DM patients IAsp lead to a larger HbA1c reduction (5 RCTs; WMD[95%CI]=-0.22% [-0.39, -0.05]) and provided superior postprandial blood glucose control. The risk of hypoglycemia, either overall or severe events was comparable between arms. CONCLUSIONS: IAsp provided better glycemic control as compared with RHI in T1DM and T2DM in patients receiving prandial insulin regimen. T1DM patients treated with IAsp were less prone to develop nocturnal hypoglycemia, while both interventions presented comparable risk of severe hypoglycemic events.