Inadequate compliance of drug intake is an important cause of ineffective pharmacotherapy and has been associated with therapeutic failure. We hypothesized that sensation seeking personality traits would affect compliance with long-term antidepressant medication. Three hundred and eight depressed patients participating in a randomized double-blind study of sertraline and citalopram were included. Personality traits were assessed using the Karolinska Scales of Personality. Compliance to medication was determined in two ways, by means of tablet counting and by measurement concentration of drug in serum. Tablet non-compliance was defined as less than 80% or more than 100% intake of the prescribed drug during weeks 20-24. Serum drug non-compliance was defined as undetectable amounts of either drug and main metabolite in the serum samples at week 24. Two virtually not overlapping groups of non-compliant patients were identified, where those regarded as non-compliant due to the interpretation of the serum drug levels were in majority. The group of serum drug non-compliant patients were recognized by significantly higher scores on the Monotony Avoidance scale and the Impulsive Sensation Seeking Psychopathy factor. The need for better methods than tablet counting and patient questioning to ascertain compliance is emphasized.