Fatty acid metabolism (FAM) genes are potentially useful for predicting prognosis and immunotherapy response in bladder cancer (BC). To examine this, we constructed a prognostic model and identified key FAM genes in BC. Using transcriptional expression profiles and clinical data of BC patients from public datasets and Changhai (CH) hospital, we built and validated a risk-score model based on 13 prognostic FAM genes. Differential gene expression identified fatty acid synthase (FASN) as central to fatty acid metabolism in BC. FASN was differentially expressed between normal and tumor tissue, and was related to survival. In the CH dataset, FASN independently predicted muscle-invasive BC. FASN differential expression was significantly related to immune-cell infiltration and patients with low FASN expression responded better to immune checkpoint inhibitor (ICI) treatment. SREBF1 was predicted as the most significant transcription factor for FASN. Competing endogenous RNA network analysis suggested that lncRNA AC107027.3 may upregulate FASN by competitively binding miR-27A-3p, thereby regulating the immunotherapy response in BC. Dasatinib and temsirolimus are potential FASN-targeting drugs. Our model efficiently predicted prognosis in BC. FASN is central to fatty acid metabolism, and a potential indicator and regulator of ICI treatment.Copyright © 2022 Xiong, Feng, Wang, Ying, Xu, Wei, Zeng and Yang.