The calpain-10 gene (CAPN10) on chromosome 2q37.3 was the first candidate gene for type 2 diabetes (T2D) identified through a genomewide screen and positional cloning. One polymorphism (UCSNP-43: G-->A) and a specific haplotype combination defined by three polymorphisms (UCSNP-43, -19, and -63) were linked to an increased risk of T2D in several populations. To quantitatively assess the collective evidence for the effects of CAPN10 on risk of T2D, we conducted a meta-analysis of both population-based and family-based association studies. We retrieved data from the MEDLINE, PubMed, and Online Mendelian Inheritance in Man databases, as well as from other relevant reports and abstracts published up to July 2003. From a total of 26 studies with primary data (21 population-based studies: 5,013 cases and 5,876 controls; 5 family-based studies: 487 parent-offspring trios), we developed a summary database that contains variables of study design, study population/ethnicity, specific polymorphisms and haplotype combinations in CAPN10, and diabetes-related metabolic phenotypes. For population-based studies, we used both fixed-effects and random-effects models to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) for the associations of CAPN10 genotypes with the risk of T2D. We also calculated weighted mean differences for the associations between CAPN10 and diabetes-related quantitative traits. Under either an additive or a dominant effect model, we found no statistically significant relation between CAPN10 genotypes in the UCSNP-43 locus and T2D risk. However, under a recessive model, individuals homozygous for the common G allele had a statistically significant 19% higher risk of T2D than carriers of the A allele (OR 1.19; 95% CI 1.07-1.33). The association between the 112/121 haplotype combination and T2D risk appeared to be overestimated by several initial small studies with positive findings (OR 1.38; 95% CI 1.04-1.84). After we removed these initial studies, this association became nonsignificant (OR 1.11; 95% CI 0.91-1.35). Moreover, we found no evidence for the associations between the UCSNP-43 G/G genotype and the 112/121 haplotype combination and metabolic phenotypes. Our meta-analysis of family-based studies showed only an overtransmission of the rare allele C in UCSNP-44 from heterozygous parents to their affected offspring with T2D. Our analysis indicates that inadequate statistical power, racial/ethnic differences in frequencies of alleles, haplotypes and haplotype combinations, potential gene-gene or gene-environment interactions, publication bias, and multiple hypothesis testing may contribute to the significant heterogeneity in previous studies of CAPN10 and T2D. Our findings also suggest that both large-scale, well-designed association studies and functional studies are warranted to either reliably confirm or conclusively refute the initial hypothesis regarding the role of CAPN10 in T2D risk.