Parietaria, a plant belonging to the family of Urticaceae, is a major source of allergenic pollen in Europe. In the context of a multinational study, we investigated whether in allergic subjects antibody response towards Par o 1, the major allergen from P. officinalis, was associated with defined HLA-DRB1* alleles. The study population consisted of 234 allergic patients: 65 from Bulgaria, 30 from Israel, 99 from Italy, and 40 from Spain. In the Italian study group, the prevalence of ST positivity to Parietaria was 77%. In Parietaria ST-positive subjects, the prevalences of IgG and IgE serum Ab towards Par o 1 were 91% and 75%, respectively. HLA-DRB1*1101 and/or 1104 were significantly positively associated with the presence of IgG Ab and with high levels of IgE Ab towards this allergen (p = 0.0007 and p = 0.012, respectively). In the Spanish study group, the positive association of DR1100 with responsiveness to Par o 1 was confirmed (p = 0.02, RR = 4, and p = 0.002, RR = 7, for IgG and IgE Ab, respectively). None of the Bulgarian patients had IgE Ab to Par o 1, whereas IgG Ab response was observed in 7 out of 65 subjects and was positively associated with DRB1*1101 and/or 1104 (p = 0.025). In the Israeli study group, responsiveness to Par o 1 was not associated with specific HLA-DRB1* alleles. In conclusion, this study shows that in allergic patients from three European populations antibody response to the major allergen from the pollen of Parietaria is associated with HLA-DRB1*1101 and/or 1104. Our data suggest that this association is stronger in subjects monosensitized to Parietaria.