Background It is generally acknowledged that pacemaker output must be adjusted with a 100% voltage safety margin above the pacing threshold to avoid ineffective pacing, especially in patients dependent on pacemakers. Aims The aim of this prospective crossover study was to assess the beat-to-beat safety of low outputs in patients who are dependent on a pacemaker between 2 follow-up examinations. Methods The study included 12 patients who had received a DDD pacemaker with an automatic beat-to-beat capture verification function. The ventricular output at 0.4 milliseconds pulse duration was programmed independently of the actual pacing threshold in a crossover randomization to 1.0 V, 1.5 V, and 2.5 V for 6 weeks each. At each follow-up, the diagnostic counters were interrogated and the pacing threshold at 0.4 milliseconds was determined in 0.1-V steps. The diagnostic pacemaker counters depict the frequency of back-up pulses delivered because of a loss of capture. During the randomization to 1.0-V output, we evaluated whether the adjustment of the output under consideration of the >100% voltage safety margin reduced the frequency of back-up pulses. Results Pacing thresholds at the randomization to 1.0-V, 1.5-V, and 2.5-V output were not significantly different, with 0.7 ± 0.3 V at 2.5-V output, 0.6 ± 0.2 V at 1.5-V output, and 0.6 ± 0.2 V at 1.0-V output. The frequency of back-up pulses was similar at 2.5-V and 1.5-V output, 2.2% ± 1.9% and 2.0% ± 2.0%, respectively. The frequency of back-up pulses significantly increased at 1.0-V output to 5.8% ± 6.4% (P <.05). Back-up pulses >5% of the time between the 2 follow-ups were observed in no patient at 2.5 V, in 1 patient at 1.5 V, and in 5 patients at 1.0 V. At the randomization to the 1.0-V output, 6 patients had pacing thresholds of 0.5 V or less, and 6 patients had pacing thresholds >0.5 V. The frequency of back-up pulses in the 2 groups was not significantly different, 6.4% ± 8.6% and 5.7% ± 2.6%. Conclusions The frequency of back-up pulses was significantly higher at 1.0-V output than at 1.5-V and 2.5-V output. This also applied to patients with pacing thresholds of ≤0.5 V. Fixed low outputs seem not to be absolutely safe between 2 follow-ups in patients who are dependent on a pacemaker, even when the output has a 100% voltage safety margin above the pacing threshold. When patients with pacemakers programmed to a low ventricular output have symptoms of ineffective pacing, an intermittent increase of the pacing threshold should be carefully ruled out. (Am Heart J 2002;143:1009-11.)