This paper examines the effect of bank, industry and macroeconomic determinants, on Southern Europe's universal bank profitability, during the period 2000-2013. Crosssectional panel data analysis is used. The results show that the measure of capital adequacy and quality of assets (internal factors) has a significant impact on bank profitability. Moreover, the effect of industry factor measured by the H.H.I. (Herfindahl index), is quite significant and has a positive impact. Additionally, in the field of macroeconomic determinants, the measure of interest rate and the measure of economic growth (macroeconomic variables) are proven statistically significant with a negative effect. Furthermore, the causality between the dependent and independent variables is examined (only for statistically significant co dependencies). The originality of this study is that, for the first time in the literature, the GDP growth rate, for the time t-1 is considered as a proxy for the macroeconomic development. The variable of GDP growth for the t-1 time is used as a precursor variable of economic growth. Though there is plenty of bibliography regarding the relationship between GDP growth proxy and profitability ratio, the results of the studies contradict each other. These inconclusive results proved there is ground for further investigation and led us to the initiative of the present study.