Sickle cell disease (SCD) pain may have a neuropathic component. Adjuvant drugs used to treat neuropathic pain have not been studied for the treatment of adults with SCD. To determine the safety and feasibility of using pregabalin for chronic SCD pain. A randomized, controlled, double-blind pilot study. Based on random assignment, participants were treated with pregabalin or placebo control for 3 months with monthly follow-up visits. Participants were recruited from the University of Illinois Hospital and Health Sciences System outpatient SCD clinic. Participants/Subjects: A total of 22 participants with SCD (21 African American, 1 other) were included 16 women aged 18–82 (mean age 33.1 ± 9.9). PAINReportIt, Leeds Assessment of Neuropathic Signs and Symptoms, Neuropathic Pain Symptom Inventory, and Short Form 36 Health Survey were completed. Adverse effects were minimal. Mean scores for average pain intensity, composite pain index, and neuropathic pain revealed a reduction for pregabalin and placebo control groups. Although the between-group differences were not significant, sustained reduction in pain over time within the pregabalin group indicated promising effects of pregabalin for SCD pain. Mean quality-of-life scores increased slightly over time (representing better quality of life) in 7 of 8 domains for the pregabalin group and decreased in 4 of 8 domains for the placebo control group. Small sample size made it difficult to interpret quality-of-life findings. This pilot study provided sufficient evidence that further investigation of pregabalin's potential efficacy for treatment of chronic SCD pain in adults is warranted.