Polysensitization against a multitude of different allergens is a common problem in the treatment of allergies with specific immunotherapy (SIT). The aim of this retrospective study was to investigate the risk of simultaneous administration of two allergen extracts during SIT with a conventional or Cluster regimen. Local (LR) and systemic reactions (SR) in 147 patients receiving different forms of SIT were compared. Patients received a total number of 2,758 injections during dose-increase phase and 3,412 injections during maintenance phase. During dose-increase phase, a higher rate of LR (for 1A 0.7% and for 2A 1.5%) was found with parallel injections of two allergen extracts (2A). The increase of SR was, however, not significant with conventional (for 1A 0% and for 2A 0.3%) or Cluster therapy (for 1A 0.3% and for 2A 0.5%). No increment of SR with injections of two allergen extracts did occur during maintenance phase (for 1A 0.3% and for 2A 0.1%). In conclusion, the results of the present study indicate that a higher rate of LR and SR must be considered during dose-increase phase independent of the kind of induction regime used. The rate of adverse events (AE) with two different allergen extracts, however, seems tolerable. After reaching maintenance phase, a higher rate of AE with parallel allergen injections did not occur.