As many as 25 percent of patients with diabetes mellitus may also have depressive symptoms. Tricyclic antidepressants (TCAs) may produce increased appetite and weight gain with adverse consequences for diabetes. The selective serotonin reuptake inhibitors (SSRIs), however, may improve fasting blood sugar in laboratory studies. In an initial application, sertraline was administered at a dose of 50 mg/day in a 10-week open study to 28 non-insulin-dependent diabetes mellitus (NIDDM) patients with DSM-III-R major depression after a 2-week single-blind placebo washout period with a minimum 17-Item Hamilton Rating Scale for Depression (HAM-D) score of 18. The patient group included 16 males and 12 females with a mean age of 54.2 +/- 8.8 years. Results indicated (1) significant improvement in mean HAM-D (22.6 +/- 3.4 to 4.9 +/- 5.9, p < .001) and in mean Beck Depression Inventory (BDI) scores (21.9 +/- 10.5 to 12.7 +/- 8.3, p < .001); (2) fall in platelet serotonin (5-HT) content (79.7 +/- 22.5 to 13.6 +/- 12.7 ng/10(8) platelets, p < .001); (3) correlation of baseline platelet 5-HT content with response to sertraline by BDI scores (r = 0.51, p < .05); (4) improved dietary compliance for those with baseline value below 70 percent (59.7% to 69.1%, p < .005); and (5) 13 of 17 patients with baseline glycosylated hemoglobin A (HbA1c) levels greater than 8.0, showed a reduction (p = .018). Sertraline may be an effective antidepressant in patients with diabetes mellitus and response may be predictable by higher baseline platelet 5-HT content, with the potential to improve dietary compliance and reduce HbA1c measures. As with all open studies, replication is essential.