Objective. There are limited comparative studies on classic and new-generation antihistamines that affect sleep quality and mood. The purpose of this study was to determine and compare the effects of classic and new-generation antihistamines on sleep quality, daytime sleepiness, dream anxiety, and mood. Methods. Ninety-two patients with chronic pruritus completed study in the dermatology outpatient clinic. Treatments with regular recommended therapeutic doses were administered. The effects of antihistaminic drugs on mood, daytime sleepiness, dream anxiety, and sleep quality were assessed on the first day and 1 month after. Results. Outpatients who received cetirizine and hydroxyzine treatments reported higher scores on the depression, anxiety, and fatigue sub-scales than those who received desloratadine, levocetirizine, and rupatadine. Pheniramine and rupatadine were found to be associated with daytime sleepiness and better sleep quality. UKU side effects scale scores were significantly elevated among outpatients receiving pheniramine. Classic antihistamines increased daytime sleepiness and decreased the sleep quality scores. New-generation antihistamines reduced sleep latency and dream anxiety, and increased daytime sleepiness and sleep quality. Conclusion. Both antihistamines, significantly increased daytime sleepiness and nocturnal sleep quality. Daytime sleepiness was significantly predicted by rupadatine and pheniramine treatment. Cetirizine and hydroxyzine, seem to have negative influences on mood states. Given the extensive use of antihistamines in clinical settings, these results should be more elaborately examined in further studies. © 2014 Informa Healthcare.