High doses of antidepressants are often used for treatment-resistant depression. Venlafaxine, a dual serotonin and noradrenaline reuptake inhibitor, has been shown to have a tolerable side-effect profile in previous studies using doses of up to 375 mg/day. We investigated the tolerability of higher than currently recommended doses of venlafaxine using the UKU side-effect rating scale. Seventy outpatients fulfilling DSM-IV criteria for major depressive disorder were recruited into two demographically matched groups according to their daily dosage of venlafaxine: high dose n = 35 (> or = 375 mg/day, range 375-600 mg, average 437 mg/day) or standard dose n = 35 (< 375 mg/day, range 75-300 mg, average 195 mg/day. Clinical characteristics were noted and the UKU side-effect rating scale was administered to a subsample of patients. The most frequently reported complaints in both groups were increased fatigue (48%), concentration difficulties (48%), sleepiness/sedation (37%), failing memory (44.4%) and weight gain (29.6%). Apart from weight gain, the complaints were found to be experienced significantly more severely by the high-dose group. Six patients discontinued venlafaxine due to intolerable side-effects but only two of these patients were on a high dose. There was a tendency for mildly raised blood pressure in 10% of patients on an average dose of 342 mg/day. However, no difference between the two groups was found. This preliminary open study demonstrates that venlafaxine is tolerated at higher than British National Formulary recommended doses (i.e. up to 600 mg daily). However, increased frequency and severity of reported side-effects in the high-dose group are not associated with increased rates of discontinuation.