Many studies have investigated whether chemical exposures early in pregnancy increase risks to women of delivering offspring with congenital anomalies. We investigated whether periconceptional exposures to chemicals in combination increased risks to women of having neural tube defect (NTD)-affected pregnancies. Women were asked about occupational tasks performed during the periconceptional period. These tasks were assigned by an industrial hygienist to a priori defined exposure categories. The exposure categories included 74 chemical groups. Two population-based case control studies were analyzed. Information on tasks was obtained from mothers of 538 NTD cases and their 539 controls in one study, and mothers of 265 NTD cases and 481 controls from another study. We used data from the first study to identify clues. Specifically, we estimated NTD risks for maternal occupational exposures to all possible pairs, triplets, and quadruplets of 74 chemical groups. Chemical combinations revealing elevated NTD risks in these "clue generation" analyses were then investigated in the second population-based case-control study for their contribution to risk of NTDs. We computed odds ratios for each of the total 192,374 possible comparisons and identified all combinations that produced odds ratios of 5 or more. A 5-fold elevated risk criterion revealed 53 combinations. These 53 reflected various combinations of exposures exclusive to 12 of 74 chemical groups. Analyses of data from the second study did not identify odds ratios of 2.0 or greater for maternal exposures to the 12 chemical groups that resulted in 5-fold elevated risks in the first study. Despite the use of a labor-intensive method to categorize exposures, we were unable to substantiate clues associated with combined chemical exposures identified in one large case-control study as NTD risk factors in a second case-control study.