Background: Venom immunotherapy (VIT) is considered to be the gold standard treatment for patients with hymenoptera venom allergy. This treatment induces systemic reactions (SR) in a significant number of patients. Objective: To evaluate the outcome of VIT in patients with known risk factors for VIT-induced SR and to compare rush VIT (RVIT) and conventional VIT (CVIT). Methods: All of the patients who received VIT and had at least one of the following risk factors were included: Current cardiovascular disease, uncontrolled asthma, high basal serum tryptase, current treatment with β-blockers or angiotensin-converting enzyme inhibitors, and age >70 or <5 years. Results: Sixty-four patients were included, and most of them (52; 81.5%) were allergic exclusively to bee venom. Thirty-five (54.7%) patients underwent RVIT and 29 CVIT. The incidence of patients who developed SR during the build-up phase was similar for RVIT and CVIT (25.7 and 27.5%, respectively; p = 1). However, the incidence of SR per injection was significantly higher in CVIT than in RVIT (5.6 and 2.75%, respectively; p = 0.01). Most reactions (79.1%) were mild, limited to the skin. Most of the patients (92.1%) reached the full maintenance dose of 100 μg. This dose was reached by a significantly larger number of patients receiving RVIT compared to CVIT (100 and 82.7%, respectively; p = 0.01). None of the patients experienced exacerbation of their concurrent chronic disease during VIT. Conclusion: VIT can be performed safely and efficiently in patients with risk factors for immunotherapy. In these patients RVIT appears to be safer and more efficient than CVIT.