Although it is generally accepted that antipsychotic treatment improves the negative symptoms of schizophrenia in the context of improvement of positive symptoms, exactly how and to what extent they effect "primary" negative symptoms remains controversial. Antipsychotic treatment may reduce only those negative symptoms secondary to positive or depressive symptoms, and may have minimal, if any effect, on negative symptoms that represent a primary psychopathological trait manifestation of schizophrenia. In an effort to further examine this issue, we prospectively assessed negative, positive, depressive, and extrapyramidal symptoms following the discontinuation of antipsychotic medication. Fifty-nine DSM III-R schizophrenic patients underwent a three-week drug wash as part of our neuroimaging protocols. We assessed psychopathological status and adverse effects utilizing various rating instruments (i.e., Scale for Assessment of Positive Symptoms [SAPS], Scale for Assessment of Negative Symptoms [SANS], Hamilton Rating Scale for Depression, and Simpson-Angus Extrapyramidal) at baseline and weekly during this three-week period. Negative symptoms, as measured by the SANS, worsened significantly during the three-week drug wash. Positive symptoms showed a less consistent change with symptoms of disorganization worsening and with psychotic symptoms remaining the same. The changes in negative symptoms during the drug-free period were correlated with the changes in psychosis and disorganization, but not with changes in depression or extrapyramidal side effects. We were not able to substantiate if the worsening in negative symptoms was a direct result of the worsening of positive symptoms or if they were changing simultaneously, but independent of each other.