In the pharmacotherapy of chronic generalized anxiety disorder (GAD) rationally grounded guidelines on the treatment to choose in individual cases are not evident in the literature. The present study was designed to address this question in 30 patients with chronic GAD. Within a period of 31 weeks, amitriptyline 30 mg/day, flupentixole 1.5 mg/day, clotiazepam 15 mg/day and placebo were administered 4 times for 1 week, double-blind and at random to each patient. U tests showed that in 19 patients one agent was superior to the other substances (p < 0.05). There was no significant difference between the drugs in 11 patients. However, a meta-analysis across all single-subject experiments showed that in individual patients suffering from chronic GAD differential effects of anxiolytic agents can be found by means of single-subject experiments (p < 0.001). The findings lend further support to the hypothesis that, in an approach to optimize pharmacological treatment of patients suffering from chronic GAD, single-subject experiments may be useful.