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The relationship between setting and individual differences in determining acute adverse reactions to psychoactive drugs was examined using retrospective data from 483 drug users. Five dimensions of setting were identified.Although there were some small setting main effects, these effects failed to reach significance when shared variance with individual difference variables was considered. For acute adverse reactions to LSD, however, there were seven independent interaction effects between setting and individual difference variables. There were two interaction effects of smaller magnitude related to acute adverse reactions to marijuana. The significance of these results for the current controversy over the relative importance of situational vs. personality determinants of behavior was discussed.