It has been shown that asthmatics have nocturnal symptoms associated with impaired cognitive performance. We explored more carefully different therapeutic approaches on this performance in relation to lung function in 46 atopics with mild to moderate asthma and with a circadian variation in peak expiratory flow (PEF) > or = 15%. In a double-blind, parallel study they inhaled salmeterol 50 microg or fluticasone 250 microg or a combination of both twice daily for 6 wk. The psychometric tests used informed about focused attention, mental flexibility, concentration, and attention. The results of the psychometric tests were compared with those in healthy control subjects. The PASAT score and the finishing time of the color-word chart subtest were significantly lower in these asthmatics than in the control subjects. Circadian PEF variation was the only independent factor significantly associated with impaired cognitive performance before the treatment period. The three treatment groups were equally effective in reducing circadian PEF variation below 10% and in improving FEV1 and bronchial hyperresponsiveness to methacholine (MCh) both day and night. After 6 wk of therapy, the daytime cognitive performance was improved to levels comparable to those of the healthy control subjects no matter which drug was inhaled. We conclude that a high level of circadian PEF variation (> or = 20%) has been associated with lower daytime cognitive performance in asthmatics. Reduction of circadian PEF variation to below 10% is an important goal of treatment in asthmatics.