Accurately evaluating alterations in sexual functioning requires a validated instrument that measures clinically relevant change over time. One-hundred one depressed patients from 15 Spanish out-patient clinics completed the Changes in Sexual Functioning Questionnaire (CFSQ; Clayton, McGarvey, & Clavet, 1997) at baseline and after 6 months of treatment with fluoxetine, nefazodone, paroxetine, or venlafaxine. Sexual desire/interest showed a nearly substantial floor effect (30% of patients indicated the maximum score) for women in the nefazodone group at baseline and in the paroxetine group at final visit. The percentage of dimensions recording change was greater for women (80%) than for men (20%) in the nefazodone group (improving changes) and greater for men (40%) than for women (20%) in the paroxetine group (worsening changes). Highest effect sizes were found on sexual desire/frequency with improvement in women in the nefazodone group (SES = 0.49), and on orgasm/ejaculation with worsening in men in the paroxetine group (SES = -1.45). In conclusion, the CSFQ is sensitive to bidirectional changes and is appropriate for measuring sexual dysfunction.