Introduction. The combination of antidepressants is a useful tool in the treatment of major depression, especially in cases where there is a partial response to antidepressant monotherapy. However, the use of this strategy is a matter of controversy, and its frequency of use in clinical practice is not clear. The aim of our study is to assess the use of antidepressants combination in Spain by reviewing three databases used between 1997 and 2001. Methods. Databases pertain to patients who are study subjects of major depression treatment. These databases are a result of studies performed in Spain and in which 550 psychiatrists participated. The total studied sample was comprised of N = 2, 842 patients, aged over 18, fitting DSM-IV criteria for Major Depressive Episode. The percentage of patients who received more than one antidepressant and the types of combinations used was described. Subsequently, a comparative study between the group which received a combination of antidepressants (N = 64) and the group which received antidepressant monotherapy (N = 775) was performed. Results. 27.1% of patients were on antidepressive monotherapy treatment, and 2.2% were on combination therapy. In the comparison of patients on combination therapy and monotherapy, there were significant differences only in episode duration (P = 0.001). The most frequent combinations are SSRIs and tricyclic antidepressants. The active principle most widely combined is fluoxetine. Conclusions. The prevalence of use of antidepressant combination therapy is 2.2% of the global sample and 8.3% of treated patients. Other than duration of the depressive episode, no clinical characteristics exclusive to patients who received combination rather than monotherapy were found. Our study found that the most frequent combination is SSRIs + TCAs, also being the most studied.