Background: Painful sensory neuropathy is a common complication of HIV infection. Based on prior uncontrolled observations, we hypothesized that amitriptyline or mexiletine would improve the pain symptoms. Method: A randomized, double-blind, 10-week trial of 145 patients assigned equally to amitriptyline, mexiletine, or matching placebo. The primary outcome measure was the change in pain intensity between baseline and the final visit. Results: The improvement in amitriptyline group (0.31 ± 0.31 units [mean ± SD]) and mexiletine group (0.23 ± 0.41) was not significantly different from placebo (0.20 ± 0.30). Both interventions were generally well tolerated. Conclusions: Neither amitriptyline nor mexiletine provide significant pain relief in patients with HIV-associated painful sensory neuropathy.