Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting complication of cancer treatment that can negatively impact survival and quality of life. Cannabidiol (CBD) has been shown to attenuate CIPN in rodent models although its ability to reduce CIPN symptoms in humans is unexplored. Methods: A phase 3 randomized double-blind, placebo-controlled clinical trial was conducted between 6/1/2020 and 8/8/2022. Participants with nonmetastatic breast, colorectal, endometrial, and ovarian cancer (all stages) experiencing grade 2-3 CIPN (duration ≤ 2 years) were enrolled after completing taxane or platin-based chemotherapy. They were randomized into active and placebo groups, and followed x 16 weeks. The active group received 135 mg/day of CBD, provided as hemp-based whole plant extract in gelcaps, while placebo consisted of coconut oil gelcaps, delivered x 12 weeks. Participants were evaluated every 2 weeks using the EORTC QLQ-CIPN20, which assesses three categories of symptoms: sensory (numbness, tingling, pain), motor (weakness, difficulty walking), and autonomic (blurriness, hearing loss). Side effect and safety data were logged daily. Results: Of 230 participants with CIPN identified, 124 met eligibility, 54 consented and enrolled, and 46 completed ≥8 of the 12-week treatment phase and were included in the analysis. Mean age was 59.6 years; 89.1% were female. Of those participants, 63% had breast cancer, 19.6% colorectal, 15.2% ovarian, and 2.2% uterine. CIPN20 scores were summated and standardized. With placebo as the reference group, main effects for sensory and motor scales were adjusted for time from enrollment and baseline CIPN grade. Participants receiving CBD had greater improvement of sensory function (p=0.048), with reduced numbness and tingling, but without significant pain reduction (p=.282) or change in motor function (p=.158) vs placebo. No autonomic changes were observed. CBD was well tolerated without serious adverse events. Conclusions: CBD reduced numbness/tingling and improved sensory function vs. placebo, as assessed by the CIPN20 scale. These symptoms are among the most common and challenging symptoms of CIPN, for which there are limited available treatment options. However, CBD did not affect pain and motor function. Thus, this preliminary study provides evidence that CBD, dosed at 135 mg/day, might serve as a treatment for some CIPN symptoms without serious adverse events. Further research is needed to confirm these results and to assess the safety and efficacy of CBD combined with chemotherapy to prevent or attenuate CIPN. Such an advance could deliver a survival benefit by helping more people complete and better tolerate chemotherapy. Clinical trial information: NCT04398446.