The safety of chronic intensive donor plasmapheresis has not been determined in large prospective studies examining dropout rates, dropout reasons and predictors of withdrawals. Twenty-one plasma centres recruited 3783 donors who were switched from a moderate to an intensive plasmapheresis programme and observed over a 3-year period. Individuals weighing < 70 kg and > or = 70 kg donated 750 ml and 850 ml of plasma per session, respectively. The maximum of annual donations was limited to 60. Total serum protein (TSP) and haemoglobin (Hb) or haematocrit (Hct) were determined at each donation, and immunoglobulin G (IgG) at every fifth donation. Dropout rates, dropout reasons and potential predictors of withdrawal were analysed. Dropouts were predominantly due to socioeconomic (49.2% of all donors) or medical reasons not related to plasma donations (10.4% of all donors). Sixteen per cent of donors dropped out when IgG, TSP or Hb levels fell below threshold values. Severe clinical adverse events related to plasmapheresis were observed in five subjects. The incidence in severe cardiovascular diseases was lower in donors than in the general population. The risk factors that led to dropping out as a result of low IgG, TSP or Hb levels included younger age, female gender, low initial IgG levels and a high donation frequency. Neither body weight nor the amounts of plasma donated per kilogram of body weight per session were associated with ceasing due to medical reasons, whether related or unrelated to plasma donations. Females and males within the respective lowest body weight category were not at higher risk of dropping out. Long-term intensive donor plasmapheresis under conditions investigated in this study is safe. All donors weighing > or = 70 kg are safely able to donate 850 ml of plasma in each session up to 60 times per year, provided that they are carefully monitored.