Background: Nighttime allergen exposures are a primary contributor to the development of allergic and asthmatic morbidities. Disease management guidelines recommend the use of environmental control measures to reduce these exposures, but clinically relevant reductions are difficult to achieve because most measures control only 1 allergen source among many in the bedroom environment. Objective: To determine whether a novel localized approach to nighttime allergen avoidance provides effective exposure reductions and clinical benefits. Methods: Thirty-five adults with perennial allergic rhinoconjunctivitis (dog, cat, or dust mite sensitivity) were randomized to receive PureZone, a combination therapy involving localized air filtration and pillow encasement, or placebo in a crossover trial with two 2-week treatment periods separated by a 1-week washout. Nasal and ocular allergy symptoms, quality of life, and breathing zone particulate exposure were assessed. Bedroom allergen dust samples were collected in the sleeping environment. Results: Reductions (>99.99%) in allergen-sized particulate (≥0.3 μm) in the breathing zone led to significant improvements in nocturnal nasal and ocular allergy symptoms (P < .001) and quality of life (P = .02) for the active vs placebo device. Significant nocturnal symptom reductions vs placebo occurred the second night of use and were maintained for the duration of treatment; these reductions improved sleep problems in particular (P = .02). Allergens were detected in 100% of bedrooms, of which 44% had levels that exceeded sensitizing thresholds. Conclusions: The combination therapy of pillow encasement and localized air filtration provided effective nighttime allergen exposure reductions and clinical benefits without the use of adjunctive therapy.