The high heterogeneity of response to antidepressant treatment in major depressive disorder (MDD) makes individual treatment outcomes currently unpredictable. It has been suggested that resistance to antidepressant treatment might be due to undiagnosed bipolar disorder or bipolar spectrum features. Here, we investigate the relationship between genetic susceptibility for bipolar disorder and response to treatment with antidepressants in MDD. Polygenic scores indexing risk for bipolar disorder were derived from the Psychiatric Genomics Consortium Bipolar Disorder whole genome association study. Linear regressions tested the effect of polygenic risk scores for bipolar disorder on proportional reduction in depression severity in two large samples of individuals with MDD, treated with antidepressants, NEWMEDS (n = 1,791) and STAR*D (n = 1,107). There was no significant association between polygenic scores for bipolar disorder and response to treatment with antidepressants. Our data indicate that molecular measure of genetic susceptibility to bipolar disorder does not aid in understanding non-response to antidepressants. © 2013 Wiley Periodicals, Inc.