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Several studies have suggested that the problem of continued patch effectiveness during long-term use could he overcome by means of an overnight patch-free interval. We believe that these studies are marred by the use of inadequate patch doses and too short an observation period of only one week during “long-term” patch application. An additional study involving more than 2(X) patients used patch doses of 10 to 40 sq cm for 4 weeks with a 12-hour on, 12-hour off regimen. The increases in exercise time compared with placebo were very small —15 to 30 s, were statistically significant only for the higher doses, and had practically disappeared by the end of the 4-week treatment period. A study monitoring the effect of nitroglycerin patches on ambulatory episodes of ST-segment depression found loss of effect by the second day despite a 12-hour overnight patch-free interval. Our own observations with ISDN titration during three times a day administration suggest that despite an overnight nitrate-free interval, most patients develop at least partial nitrate tolerance, and a significant number go on to develop complete tolerance to conventional doses. We believe that the key to maintaining persistent patch effectiveness is adequate dose, and not just a nitrate-free interval. Even with intermittent dosing and a nighttime nitrate-free interval, as is the case with ISDN administration, patients become at least partially nitrate tolerant.