In the current investigation, the authors examined the diagnostic construct validity of the Minnesota Multiphasic Personality Inventory–2–Restructured Form (MMPI-2-RF) in a patient sample. All participants were diagnosed via the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I/P). The data set used in this study was composed of 544 patients—67 with bipolar disorder, 407 with major depressive disorder, and 70 with schizophrenia. Multivariate analyses revealed a pattern of mean scale differences among patient groups that was mostly consistent with the prominent features of each diagnostic group; logistic regression analyses identified a number of scales that were strong, unique predictors in the differentiation between pairs of diagnostic groups. The higher order scales (H-O)—the Emotional/Internalizing Dysfunction (EID) and Thought Dysfunction (THD) scales were most useful in differentiating between patient groups. For differentiating bipolar disorder patients from the other diagnostic groups, the Activation (ACT) Specific Problem scale was most useful. Although not all hypothesized scale differences emerged; overall, the pattern of results provides support for the diagnostic construct validity of the MMPI-2-RF scales.