Objective: Cognitive alterations in bipolar disorder may reflect genetic influence. However, to what degree mood, medication, thyroid function and other factors impact on longitudinal cognitive functioning remains unclear. Method: A group of patients with bipolar (spectrum) disorder (n=76) underwent two monthly cognitive assessments over a 2-year period in a prospective, repeated measures design. Regression models were used to investigate associations with predictors, corrected for multiple testing. Results: Patients with bipolar disorder performed worse than healthy controls (n=61) on all cognitive domains tested. Effect sizes were small, with a maximum of -0.36 for sustained attention. However, cognitive performance varied substantially over the 2-year follow-up, co-varying with subjective cognitive complaints and impacting on functioning. Alterations in sustained attention and motor speed were the only impairments that were invariant over time. Predictors had very limited explanatory power on temporal variation in cognition. Use of second-generation antipsychotics was associated with the largest negative effects on cognition, which were evident in the areas of motor speed and basic information processing (-0.35<β<-0.5). Conclusion: Cognitive function in bipolar disorder varies significantly over time, largely independent of clinical factors. The temporal stability of sustained attention is the exception, suggesting it may represent a possible candidate intermediary phenotype. © 2010 John Wiley & Sons A/S.