Studies on the association between the functional uMAOA polymorphism and depression have yielded non-conclusive results up till now. One thousand two hundred twenty eight consecutive Spanish primary care attendees, participating in the PREDICT study, agreed to take part in this genetic PREDICT-Gene study. We explored the association between depression and either high-activity uMAOA alleles or genotypes. Depression was diagnosed using the Composite International Diagnostic Interview (CIDI) to establish three different depressive outcomes (ICD-10 Depressive Episode (DE), ICD-10 Severe Depressive Episode (SDE) and DSM-IV Major Depression (MD)). uMAOA genetic variation was determined by PCR amplification and subsequent electrophoresis. Crude and adjusted (gender and/or age) odds ratios, with 95% confidence intervals, were calculated for the associations between allele or genotype frequencies and all three depressive outcomes. We found associations between all three depressive phenotypes and either high-activity alleles or high-activity genotypes in both sexes. The associations were statistically significant for females but not for males. Testing the same associations on the entire sample (males and females) also yielded significant associations between depression and either high-activity alleles or high-activity genotype distribution that were independent of age and/or gender (ICD-10 DE: OR = 1.98; 95% CI: 1.42-1.77; P = 0.00002; ICD-10-SDE: OR = 2.05; 95% CI: 1.38-3.05; P = 0.0002; DSM-IV MD: OR = 1.91; 95% CI: (1.26-2.91); P = 0.0014). Our results provide fairly consistent evidence that high-activity variants of the MAOA promoter polymorphism confer a modestly higher risk for depression.