Regional patterns of health data such as cancer incidence rates are often examined for evidence of environmental effects. In this paper, three measures of spatial clustering are evaluated for use with epidemiologic data. In particular, the effects of variation in regional population structure on the distribution of these measures is considered. It is shown that substantial bias occurs if variation in regional population size is ignored (as has occurred in previous analyses). On the other hand, the methods are robust to small case frequencies and to variation in the regional age distribution. It is recommended that these regional differences be routinely taken into account, which can be done with relatively little additional computation. A companion paper (Walter SD. The analysis of regional patterns in health data. II. The power to detect environmental effects.