This study investigated the specificity and efficacy of immunotherapy with Artemisia vulgaris (Artemisia) extract. We studied 25 patients with a more than two year lasting history of seasonal rhinoconjunctivitis and who had only two clinically important allergies, either to Artemisia and Betula verrucosa (Betula) or to Artemisia and Phleum pratense (Phleum). Patient selection was randomized and evaluation of results was conducted in double blind fashion. Twenty patients completed two years of specific immunotherapy. Nine patients were treated with extracts of Artemisia and 11 with extracts of either Betula (n = 3) or Phleum (n = 8). Treatment with Artemisia was followed by a significant decrease in skin sensitivity (p < 0.05) and eye sensitivity (p < 0.01) to Artemisia but not to Betula/phleum. No significant decrease was observed in medicine consumption or symptom scores. Patients treated with Betula or Phleum experienced a significant decrease in skin sensitivity to Betula or Phleum (p < 0.001), and eye sensitivity to Betula or Phleum (p < 0.05), but not to Artemisia and had significant decreases in medicine and symptom scores (p < 0.05) in Betula/phleum seasons but not in the Artemisia season. The treatment was both effective and specific with the one unexplained exception that both patient groups (Artemisia and Betula/Phleum) decreased their skin sensitivity to Artemisia.