Background: CRCI is an important clinical problem encompassing difficulties in attention, memory, and executive function. Interventions for CRCI during chemotherapy have not been established. Inflammation is associated with CRCI and thus targeting inflammation may alleviate CRCI. In a nationwide study, we investigated a low-dose of ibuprofen for alleviating CRCI in patients self-reporting cognitive problems during chemotherapy or after recent completion of chemotherapy. Methods: Participants with cancer currently on or recently completed chemotherapy and who self-reported cognitive problems were recruited via the NCI Community Oncology Research Program (URCC NCORP) and 11 affiliates. Participants completed pre-intervention assessments and were stratified by disease type (breast cancer; gastrointestinal cancer; other) and randomized to one of 2 groups for 6 weeks: ibuprofen (200 mg BID) or blinded placebo equivalent. At pre-intervention and post-intervention, participants completed a perceived cognitive function measure (FACT-Cog Perceived Cognitive Impairment (PCI)) and cognitive assessments including Rapid Visual Processing (RVP) latency, Delayed Match to Sample (DMS) visual memory, and Verbal Recognition Memory (VRM) word recall. ANCOVA was used to assess between group differences pre- to post-intervention adjusting for baseline cognitive test score. Results: In total, 87 participants were randomized; 45 were randomized to ibuprofen and 42 randomized to placebo (mean age = 55; 85% female; 47% breast cancer, 29% colon/colorectal cancer; 24% other diagnoses). Most participants were fully compliant and completed post-intervention assessments (86% in Ibuprofen arm, 87% in placebo arm). There were no gastrointestinal bleeding events of any grade in the ibuprofen arm and serious adverse events were rare in both arms occurring in only 4% and 7% of patients in the ibuprofen and placebo arms, respectively. For PCI, both groups significantly reported less impairment from pre- to post-intervention; there were no difference between groups. Patients randomized to ibuprofen had a significant improvement on RVP latency time compared to placebo (110.63 milliseconds; p < 0.005). On the DMS, patients receiving ibuprofen had a trend toward improved function compared to placebo (7.39%; p = 0.08). However, patients in placebo performed better in word recall compared to ibuprofen from pre- to post-intervention (1.64 words; p < 0.05). Conclusions: Low-dose, short duration ibuprofen was safe with minimal adverse events in patients with cancer receiving chemotherapy or recently completed chemotherapy. Ibuprofen showed improvements in processing speed time and visual memory in patients with cancer as hypothesized, but not verbal memory. These novel Phase II findings need to be replicated in a Phase III RCT. Funding: R21CA187500, UG1CA189961. Clinical trial information: NCT03186638.