An exploratory case-control study of paternal occupation as a risk factor for Down syndrome was conducted. With the use of the British Columbia Health Surveillance Registry, 1,008 cases of live-born Down syndrome were identified for the period 1952-73. Two controls were matched to each case by using the birth files of British Columbia. Paternal occupation was obtained from the birth notice. Elevated maternal age-adjusted relative risks of Down syndrome were found for fathers employed as janitors (odds ratio [OR] = 3.26; 95% confidence interval [C.I.] = 1.02-10.44); mechanics (OR = 3.27; C.I. = 1.57-6.80); farm managers/workers (OR = 2.03; C.I. = 1.25-3.03); material-moving equipment operators (OR = 1.88; C.I. = 0.93-3.82); food processors (OR = 1.79; C.I. = 0.96-3.31); sheet-metal workers, iron workers, and other metalworkers (OR = 1.57; C.I. = 0.92-2.69); and sawmill workers (OR = 1.43; C.I. = 0.90-2.66). This large study provides new leads for further evaluation of the role of paternal exposures in the etiology of Down syndrome.