Purpose À This paper examines the profitability and performance measurement of U.S. regional banks during the period 1994À2011, using the GMM estimator technique. Our study extends prior research by including several factors not previously considered using U.S. data.Approach À We use bank-specific, industry-specific, and macroeconomic determinants of profitability contemporaneous with our performance indicators. We follow the accounting fundamental analysis path in explaining the bank performance.Findings À Among the performance measures, the efficiency ratio and provisions for credit losses are negatively and equity scaled by assets is positively related to profitability. However, these relationships either reverse (efficiency ratio and provisions for credit losses) or become insignificant (equity scaled by assets) when the target becomes change in profitability. The level of nonperforming assets is negatively related to profitability across all measures of profitability used. Macroeconomic variables are largely unrelated to profitability during the year they are measured. However, they have a significant relationship with earnings change measures, suggesting they have a lagged effect on profitability. The slope of the yield curve is especially strong in this regard.Originality À We use our determinants to model changes in bank profitability one year ahead, in addition to including several factors not previously considered, using the predictive focus of the fundamental analysis research.Keywords: Banking profitability; return on assets (ROA); return on equity (ROE); efficiency ratio; macroeconomic factors; fundamental analysis research LITERATURE REVIEWWe review the literature on the determinants of bank profitability. Because of its widespread acceptance, for the sake of conciseness, and to facilitate comparisons across studies, we cite ROA results unless otherwise specified. We will also describe the approach of fundamental analysis to earnings prediction. Geographic Scope of Banking Profitability StudiesSeveral studies have focused on bank profitability in individual countries. Single country studies are of