This study compared fluency changes in adult developmental stuttering speakers treated with two tricyclic antidepressants, clomipramine and desipramine. Clomipramine is primarily a serotonergic reuptake inhibitor, and desipramine, primarily a noradrenergic reuptake inhibitor. Sixteen subjects who stuttered participated in a single-blind placebo, double-blind active drug crossover study lasting 12 weeks. Speech rate and percent fluency did not significantly improve in placebo compared to baseline. Speech rate significantly increased while repeating, reading or constructing sentences, and during a telephone conversation, but no significant changes in percent fluency were found under clomipramine compared to placebo. Speech rate during a telephone conversation and percent fluency while speaking in front of an audience of four to seven listeners significantly increased under clomipramine compared to desipramine. No significant improvements in percent fluency or speech rate were found for any speaking task under desipramine compared to placebo. Twelve of 16 subjects reported improved fluency compared to baseline using clomipramine, whereas 6 reported improvement using desipramine. Because more evidence of improvement was found under clomipramine compared to desipramine, fluency improvement may be related to clomipramine's greater selectivity for serotonergic reuptake inhibition.