It has been suggested that the ratio of tryptophan (TRP) and tyrosine (TYR) to other large neutral amino acids may predict response to antidepressant drugs with predominantly serotonergic compared with predominantly noradrenergic activity and that this may be clinically useful. 147 subjects with a DSM-III-R diagnosis of major depression underwent a detailed clinical evaluation and prior to treatment had baseline measures of TRP, TYR and other large neutral amino acids (LNAA), prolactin and cortisol. Subjects entered a 6-week randomised treatment trial comparing fluoxetine and nortriptyline. There was no main effect on 6-week outcome of TRP/LNAA ratio or TYR/LNAA ratio and no interaction between these factors and treatment (fluoxetine vs nortriptyline). Alterations in antidepressant dose were allowed therefore possibly reducing the effect of TRP or TYR availability on response. Previous findings that TRP/LNAA and TYR/LNAA ratios may predict differential response to antidepressants were not replicated and neither was our previous finding of a complex relationship between TRP/LNAA and baseline prolactin in predicting 6-week response.