The objective was to identify predictors of cognitive decline in patients with hypoxaemic COPD on continuous oxygen therapy. Eighty-four consecutive ambulatory hypoxaemic COPD patients in stable clinical conditions were prospectively studied over the course of 2 yr. Baseline multidimensional assessment included respiratory function tests, blood gas analysis, Mini Mental Status (MMS) test, Geriatric Depression Scale (GDS), Activities of Daily Living (ADLs) and Charlson's index of comorbidity. Reassessments were made 1 yr and 2 yr thereafter. Sequential changes in MMS, GDS and ADLs were assessed by Friedman's ANOVA by rank test. Forty patients completed the study (group A), while 44 died or were lost to follow-up (group B). Group B was characterized by more severe respiratory function impairment and worse performances on ADLs and GDS. In group A, MMS deteriorated from baseline to the 1 yr and 2 yr reassessments (27 +/- 2.9 vs. 25.8 +/- 4.1 and 25.4 +/- 4, P < 0.005), whereas GDS and ADLs did not change significantly; the 23 patients experiencing a decline of MMS had baseline lower percentage predicted FVC (52.3 +/- 17.1 vs. 66.9 +/- 13.4, P < 0.03) and FEV1 (27.2 +/- 8.6 vs. 44 +/- 26.8, P < 0.02) values and better affective status (GDS score: 11.9 +/- 7.7 vs. 16.5 +/- 5.6, P < 0.04). Two-year changes in MMS and in GDS scores were inversely correlated (Spearman's p = -0.32, P = 0.04). Cognitive decline is faster in the presence of severe bronchial obstruction and parallels the worsening of the affective status in COPD patients on oxygen therapy. The onset of depression rather than baseline depressive symptoms seems to be a risk factor for cognitive decline.