INTRODUCTION: Efforts to map quantitative trait loci (QTLs) across human tissues by the GTEx Consortium and others have identified expression and splicing QTLs (eQTLs and sQTLs, respectively) for a majority of genes. However, these studies were largely performed with gene expression measurements from bulk tissue samples, thus obscuring the cellular specificity of genetic regulatory effects and in turn limiting their functional interpretation. Identifying the cell type (or types) in which a QTL is active will be key to uncovering the molecular mechanisms that underlie complex trait variation. Recent studies demonstrated the feasibility of identifying cell type–specific QTLs from bulk tissue RNA-sequencing data by using computational estimates of cell type proportions. To date, such approaches have only been applied to a limited number of cell types and tissues. By applying this methodology to GTEx tissues for a diverse set of cell types, we aim to characterize the cellular specificity of genetic effects across human tissues and to describe the contribution of these effects to complex traits. RATIONALE: A growing number of in silico cell type deconvolution methods and associated reference panels with cell type–specific marker genes enable the robust estimation of the enrichment of specific cell types from bulk tissue gene expression data. We benchmarked and used enrichment estimates for seven cell types (adipocytes, epithelial cells, hepatocytes, keratinocytes, myocytes, neurons, and neutrophils) across 35 tissues from the GTEx project to map QTLs that are specific to at least one cell type. We mapped such cell type–interaction QTLs for expression and splicing (ieQTLs and isQTLs, respectively) by testing for interactions between genotype and cell type enrichment. RESULTS: Using 43 pairs of tissues and cell types, we found 3347 protein-coding and long intergenic noncoding RNA (lincRNA) genes with an ieQTL and 987 genes with an isQTL (at 5% false discovery rate in each pair). To validate these findings, we tested the QTLs for replication in available external datasets and applied an independent validation using allele-specific expression from eQTL heterozygotes. We analyzed the cell type–interaction QTLs for patterns of tissue sharing and found that ieQTLs are enriched for genes with tissue-specific eQTLs and are generally not shared across unrelated tissues, suggesting that tissue-specific eQTLs originate in tissue-specific cell types. Last, we tested the ieQTLs and isQTLs for colocalization with genetic associations for 87 complex traits. We show that cell type–interaction QTLs are enriched for complex trait associations and identify colocalizations for hundreds of loci that were undetected in bulk tissue, corresponding to an increase of >50% over colocalizations with standard QTLs. Our results also reveal the cellular specificity and potential origin for a similar number of colocalized standard QTLs. CONCLUSION: The ieQTLs and isQTLs identified for seven cell types across GTEx tissues suggest that the large majority of cell type–specific QTLs remains to be discovered. Our colocalization results indicate that comprehensive mapping of cell type–specific QTLs will be highly valuable for gaining a mechanistic understanding of complex trait associations. We anticipate that the approaches presented here will complement studies mapping QTLs in single cells.