Indirect evidence suggests there may be early influx of beta-cell-directed macrophages into the islets of NOD mice, and before the onset of T-cell insulitis. We have therefore examined immunohistochemically the pancreas of young female NOD mice with monoclonal antibody F4/80 for the presence of macrophages in intraislet, peri-islet, exocrine, and perivascular regions preceding insulitis (days 18 and 22) and during early insulitis (days 30 and 40) and compared their distribution in age-matched normal Swiss mouse pancreas. In the absence of insulitis (day 18 and day 22) and during very early insulitis (day 30) macrophage-positive cells had a predominantly exocrine and perivascular distribution with reduced numbers in the peri-islet area. Intraislet macrophages usually occurred singly and were sparse. At day 40, an enhanced influx of the immune cells was observed in intra- and peri-islet locations and in parallel with increased numbers in the exocrine areas. At this age, higher numbers of macrophages were observed within the islet, distributed among the T-cell infiltrate and also scattered among the endocrine cells. During the study period, the number of macrophages in the peri-, intraislet, and exocrine regions was significantly higher among NOD mice than in the Swiss mouse group (p = 0.003, p = 0.005, and p = 0.0009, respectively). In the absence of insulitis (days 18 and 22), although the number of positive cells tended to be higher in NOD mice, this difference reached statistical significance in the peri-islet area (p = 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)