We investigated whether outdoor-cultivated Agaricus brasiliensis (KA21) could reduce the side effects caused by the anticancer medicine 5-fluorouracil (5-FU). The adverse effects of 5-FU were analyzed in mice by orally administering the drug every day for 5 days. Leukopenia, diarrhea, body weight loss, anorexia, kidney injury, gastrointestinal tract injury, and hair loss were evaluated as side effects. We determined whether these side effects were reduced by the intake of outdoor-cultivated A. brasiliensis. The side effects were reduced in mice receiving the outdoor-cultivated A. brasiliensis but not in those receiving the indoor-cultivated A. brasiliensis. These results suggest that outdoor-cultivated A. brasiliensis is beneficial in reducing the side effects of the anticancer medicine and might, therefore, be useful in improving the quality of life of patients with cancer. Furthermore, because antioxidants have been reported to contribute to the suppression of the side effects of anticancer medicines, the antioxidant activities of different mushrooms were determined. The antioxidant activity of the outdoor-cultivated A. brasiliensis was the highest among all the tested mushrooms. These findings make it clear that the cultivation conditions of A. brasiliensis are important in suppressing the side effects of anticancer medicines. Strong antioxidant activity might be one of the mechanisms through which this pharmacological activity is mediated.