Few current data are available regarding the political behavior of American physicians as the number of female physicians has increased and the number of solo practitioners has decreased. To analyze campaign contributions that physicians made from the 1991 to 1992 through the 2011 to 2012 election cycles to Republican and Democratic candidates in presidential and congressional races and to partisan organizations, including party committees and super political action committees (Super PACs). We explored partisan differences in physician contributions by sex, for-profit vs nonprofit practice setting, and specialty using multiple regression analysis. We studied the relation between the variation in the mean annual income across specialties and the mean percentage of physicians within each specialty contributing to Republicans. Differences in contributions to Republicans and Democrats, for all physicians and for subgroups. Between the 1991 to 1992 and the 2011 to 2012 election cycles, physician campaign contributions increased from $20 million to $189 million, and the percentage of active physicians contributing increased from 2.6% to 9.4%. Of physicians who contributed during the study period, the mean percentage contributing to Republicans was 57% for men and 31% for women. Since 1996, the percentage of physicians contributing to Republicans has decreased, to less than 50% in the 2007 to 2008 election cycle and again in the 2011 to 2012 election cycle. Contributions to Republicans in 2011 to 2012 were more prevalent among men vs women (52.3% vs 23.6%), physicians practicing in for-profit vs nonprofit organizations (53.2% vs 25.6%), and surgeons vs pediatricians (70.2% vs 22.1%). In 1991 to 1992, these contribution gaps were smaller: for sex, 54.5% vs 30.9%; for organizations, 54.2% vs 40.0%; and for specialty, 65.5% vs 32.7%. The percentage of physicians contributing to Republicans across specialties correlated 0.84 with the mean log earnings of each specialty; specialties with higher mean earnings had higher percentages of physicians contributing to Republicans. Between 1991 and 2012, the political alignment of US physicians shifted from predominantly Republican toward the Democrats. The variables driving this change, including the increasing percentage of female physicians and the decreasing percentage of physicians in solo and small practices, are likely to drive further changes.