In this study, the success of 6,054 college students "screened" as twice-exceptional (2e; i.e., those with significantly discrepant math vs. reading scores on the ACT [formerly, American College Test] or SAT [formerly, Scholastic Aptitude Test]) was examined based on major selection and type of potential learning disability using a screening technique proposed by McCallum et al. There were no differences in high school grade point average, college grade point average, or first-year retention rates between students screened as 2e who had a major in line with their academic strength versus those who did not (p > 0.05). However, students screened as 2e based on an exceptionally high math score but a lower reading score yielded statistically significantly higher rates of retention (p < 0.05) than students screened as 2e with the reverse pattern of scores (i.e., gifted in reading with a potential learning disability in math). Implications for screening 2e students are discussed.