A double-blind, placebo-controlled study of immunotherapy was conducted in 19 patients with grass-pollen hay fever to evaluate the efficacy and safety of a formalinized depot grass allergoid. The patients were assessed before and during IT by clinical (symptom-medication scores during the grass- pollen season, specific nasal and skin reactivity) and immunological (specific IgE, IgG, IgG1 and IgG4 antibodies) parameters. High doses of grass allergoid, corresponding to a cumulative pre-seasonal dosage of 46050 PNU, were administered, with only one systemic reaction. The actively treated patients had significantly lower symptom-medication scores than placebo (p < 0.01) during the month of May and showed a significant decrease in specific skin (p < 0.01) and nasal (p < 0.05) reactivity, and a significant early increase in specific IgE (p < 0.01), IgG (p < 0.0005), IgG1 (p < 0.001) and IgG4 (p < 0.05), with a subsequent decrease of IgE and IgG1. No differences were detected in any of these parameters in the placebo group. A correlation was found between high IgG4/IgG1 ratio and the specific skin reactivity decrease (r = 0.691, p < 0.05), whereas a high IgG4/IgG1, ratio was associated with higher symptom-medication scores (r = 0.654, p < 0.05). Possible explanations of these apparent discrepancies are proposed.