Histamine N-methyltransferase (HNMT) catalyzes the N tau-methylation of histamine. HNMT is present in many human tissues, including the red blood cell (RBC). Our study evaluated the possible role of inheritance in the regulation of individual variations in human RBC HNMT activity. HNMT activity was measured in RBC lysates from 241 members of 51 nuclear families. After correction for the gender-specific effects of age, the frequency distribution of RBC HNMT activities was unimodal, and activities varied threefold within 2 SDs of the mean. The correlation of HNMT activities in RBCs from 45 pairs of spouses was only 0.070, indicating that shared environment did not result in similar activities among genetically unrelated individuals. Correlation coefficients were also calculated for pairs of genetically related individuals. All of these correlations were significant except the mother-oldest son correlation. The majority of the correlations did not differ significantly from those predicted for a trait with a heritability of 1.0 (100%). Our results demonstrate a significant familial aggregation of human RBC HNMT activity and suggest that inheritance may play an important role in the regulation of variation in the activity of this N-methyltransferase enzyme in the human RBC.