Few risk factors for quality-of-life outcomes of simultaneous pancreas and kidney transplant recipients are known because of a paucity of data from prospective studies. Pretransplant assessment and prospective 3-year follow-up. Consecutive potential recipients at a university teaching hospital assessed by Liaison Psychiatry. Demographic data; pretransplant Transplant Evaluation Rating Scale scores; current, past 12 months, and prior lifetime psychiatric disorder. 36-Item Short Form Health Survey (SF-36) scores. 37 simultaneous pancreas and kidney transplant recipients were assessed pretransplant and at 4 months posttransplant. Posttransplant at 1 year, 29 (81% of survivors); at 2 years, 26 (79% of survivors and those reaching 2 years); and at 3 years, 22 (92% of survivors and those reaching 3 years) patients were assessed. SF-36 Mental Component Summary (MCS) scores (mean pretransplant, 46.8 +/- 8.2 [SD]; 4 months, 51.7 +/- 8.5; 1 year, 50.1 +/- 9.7; 2 years, 51.8 +/- 8.9; and 3 years, 50.8 +/- 13.8) and Physical Component Summary (PCS) scores (pretransplant, 40.6 +/- 10.6; 4 months, 43.6 +/- 12.0; 1 year, 45.6 +/- 11.3; 2 years, 48.1 +/- 10.2; and 3 years, 46.8 +/- 9.1) showed sustained improvement posttransplant. MCS scores became similar to population norms. Functionally significant decreases in MCS and PCS scores were seen in 4%-21% and 8%-30% at times posttransplant. Male sex predicted higher scores at 4 months for the MCS (P = 0.003; regression coefficient, -8.28 [95% CI, -13.6 to -2.9]; effect size, 0.22) and PCS (P = 0.05; regression coefficient, -6.91 [95% CI, -13.9 to 0.9]; effect size, 0.08). Current psychiatric disorder at pretransplant evaluation predicted higher PCS scores at 4 months (P = 0.002; regression coefficient, -15.42 [95% CI, -24.6 to -6.2]; effect size, 0.22) and 1 year (P = 0.002; regression coefficient, -17.3 [95% CI, -27.9 to -6.7]; effect size, 0.29). Psychiatric disorder before the 12 months before the pretransplant evaluation predicted lower PCS scores at 4 months posttransplant (P < 0.001; regression coefficient, 14.98 [95% CI, 7.1-22.8]; effect size, 0.29). Cohort size. Although half experienced sustained quality-of-life improvement, up to one-third experienced a decrease. Past psychiatric disorder is a risk factor. Patients should be educated and monitored appropriately.