Background Although antiinflammatory therapy is accepted as the cornerstone of asthma treatment, available systemic immunosuppressive agents are not widely used because of justified concerns over potential toxicity. Hydroxychloroquine (HCQ) is a well-tolerated, safe immunomodulating drug, with proven efficacy in rheumatic diseases and known actions that suggest potential utility in the treatment of asthma. Objective: We sought to assess the effectiveness of HCQ in subjects with moderate symptomatic asthma. Methods: Symptomatic asthmatic subjects receiving stable doses of at least 6 puffs of inhaled corticosteroid per day with daily need for β₂-adrenergic agonists were studied. After baseline run-in, these subjects were randomized to 30 weeks of HCQ (n = 8) or placebo (n = 9). Objective measures included change from baseline mean FEV₁, morning and evening peak flows, β₂-agonist use, IgE level, and need for rescue cortico-steroids. Subjective symptom scores from bidaily diaries were also obtained. Results: In the treatment group, mean FEV₁ at the last 2 visits on therapy increased by 10.8% (P < .05), morning peak flows rose 16.2% (P < .03), evening peak flows rose 14.2% (P < .04), and β₂-agonist use fell 18.6% (P < .03). Mean IgE level declined 48% from 240 to 125 IU/mL (P < .05). In the placebo group no significant change in these parameters occurred. Comparison of changes in these objective measures between the treatment and placebo groups failed to reach significance in the small population studied. Corticosteroid rescue interventions were required in 4 patients receiving placebo and 2 receiving HCQ. HCQ was well tolerated without notable side effects. Conclusions: Although the size of our sample population precludes definitive conclusions, these findings extend previous open-label observations. The late improvement in the HCQ group is consistent with its known slow onset of action. Further studies are warranted to confirm the antiasthmatic and antiallergic effects of HCQ and to investigate its potential as a disease-modifying agent. (J Allergy Clin Immunol 1998;102:198-203).