Background: Over half of patients receiving “neurotoxic” taxane, platinum, or bortezomib chemotherapy experience CIPN—a dose-limiting toxicity involving numbness and pain in the extremities. There are no FDA-approved drugs for CIPN, but exercise may help. This randomized pilot study explored whether structured exercise during chemotherapy ameliorates CIPN symptoms and whether improvements involve changes in the brain’s sensory processing (interoceptive) circuitry. Methods: Nineteen patients scheduled to receive taxane, platinum, or bortezomib were randomized to exercise (home-based, low-moderate intensity, walking and resistance training; EXCAP) or nutrition education (control) for 12 weeks starting at their first infusion. At 0, 6, and 12 weeks, we assessed CIPN symptoms using the CIPN-20 questionnaire (sensory scale, ranges 9-36, higher is worse) and a finger tactile sensitivity task. We assessed resting functional connectivity between the insula and thalamus via fMRI at 0 and 12 weeks. We used linear regression to model each outcome, tested for an effect of exercise, and controlled for baseline value and age because controls were older. Given the pilot nature of this study we present effect sizes, not p-values. Results: The 19 patients were 65±11 years old, 52% women, with cancer: 42% breast, 32% gastrointestinal, 16% myeloma, and 10% genitourinary. Exercise mitigated CIPN symptoms per the CIPN-20 sensory scale. At 6 weeks, exercisers increased from 11.0 to 12.5 whereas controls increased from 11.0 to 15.5 (+1.5 vs. +4.5; ES = 0.81). At 12 weeks, exercisers increased from 11.0 to 14.8 whereas controls increased from 11.0 to 16.2 (+3.8 vs. +5.2, ES = 0.46). The finger-touching test corroborated results at 6 and 12 weeks (ES = 1.03 and 0.07). Exercisers showed better (reduced) insula-thalamus connectivity vs. controls (ES = 0.41). Reductions in connectivity were correlated with smaller increases in CIPN symptoms (r = 0.74). Conclusions: Exercise during neurotoxic chemotherapy mitigated CIPN symptoms, perhaps via improvements in interoceptive brain circuitry. Future work should test for replication with a larger sample. Clinical trial information: NCT03021174