• This study examined the potential side effects of theophylline on behavior, attention, memory, and fine motor function in children with asthma. Seventeen children of normal intelligence who were intermittent theophylline users were recruited. Each was not taking medication at the initiation of the study. During the study, each child took the study medication (Theo-Dur tablets, 14 to 16 mg/kg per day or their usual dose, whichever was higher, or placebo) divided every 12 hours for 3½ days (seven doses). A double-blind crossover design was employed such that each subject was randomly assigned to a group receiving theophylline/placebo or placebo/theophylline. After the first period, subjects were tested on a neuropsychological battery designed to assess cognitive performance, while the children, parents, and teachers filled out questionnaires concerning behavior and attention. The same procedure was repeated two weeks later (period 2) under the opposite drug condition. Data were analyzed by means of an analysis of variance, with time (period 1 vs period 2 [performance]) as a repeated measure and medication group as a between-subjects factor. Dependent variables consisted of 27 measures of performance, behavior, and attention. Only one of the 27 analyses revealed a significant group by time interaction. This analysis suggested a significant improvement in memory while taking theophylline; however, a different form of the same test showed no effect. Children and parents also completed a side-effects scale under both drug conditions. When the children were taking theophylline, parents and children noted that the children had more stomachaches and children noted more "shaking hands." The following observations suggest that the failure to find significant behavioral side effects while taking theophylline is not due to the relatively small sample size: (1) Almost all of the analyses fell far short of statistical significance, with findings indicating no trends toward poor performance while taking medication. (2) Correlations between the theophylline level and change in performance clustered around zero, with positive and negative values occurring with about equal frequency. (3) Neither parents nor children could accurately guess the child's medication condition. Thus, although there have been numerous reports on the behavioral side effects of theophylline, such reactions were not revealed in this study.