BACKGROUND: The efficacy and safety of short-term immunotherapy with molecular standardized allergens (STI) has been demonstrated by double-blind placebo-controlled clinical trials. The aim of this study was to compare STI with symptomatic drug treatment. METHODS: Forty-eight patients with rhinoconjunctivitis to grass and/or rye pollen were treated either with STI (ALK7, n = 24) plus anti-allergic drugs or anti-allergic drugs, alone (n = 24) in a prospective, randomized study. Symptoms and use of drugs were reported in patient diaries and titrated nasal provocation and skin prick tests were performed at baseline, before, and after season. RESULTS: Median overall symptom ( P = 0.022, U test) and medication scores ( P = 0.003) were significantly lower in the STI group, as was the result for a simultaneous analysis of conjunctival, nasal, and bronchial symptom scores and medication ( P = 0.005). Sensitivity in the nasal provocation test decreased in the STI group but not in the drug-treated group. These differences became significant directly after STI ( P = 0.027) as well as after the grass pollen season ( P < 0.001). Skin sensitivity did not change in the STI group but increased in the drug-treated group after season, with a significant difference between the two groups for the erythema ( P < 0.001). CONCLUSIONS: STI reduces grass pollen-induced rhinoconjunctivitis symptoms and drug use, and specific nasal reactivity and skin sensitivity, more efficiently than a standard symptomatic treatment.