Post-heparin lipoprotein lipase and hepatic lipase activities are used to identify primary disorders of triglyceride and HDL-cholesterol metabolism. Their ability to identify common variants in the lipoprotein lipase (LPL) and hepatic lipase (LIPC) genes is unclear. To investigate the ability of lipase testing to detect common lipase gene variants, we included 183 patients who had undergone post-heparin lipase testing and genotyped the LPL D9N, N291S, PvuII, HindIII, and S447X and the LIPC-514CT, V73M, V133V, and N193S polymorphisms. Allele frequencies were compared with 163 controls. Polymorphisms with different allele frequencies in patients and controls or influencing lipids, were analyzed further. The diagnostic value of post-heparin lipase testing was assessed using logistic regression and receiver operating characteristic curves. We found that lipase activities did not predict the LPL D9N and N291S polymorphisms, but predicted the LPL S447X and LIPC-514CT polymorphisms. Adjusted for covariates, the area under the receiver operating characteristic curves was 0.643, 0.478, 0.686, and 0.657 for LPL D9N, N291S S447X and LIPC-514CT, respectively. On the basis of these findings, we conclude that high-LPL and low-HL activities associate with the LPL S447X and LIPC-514CT polymorphisms, but low-LPL activity was not related to LPL polymorphisms. Overall, the discriminative ability of post-heparin lipase tests in identifying carriers of common variants in the LPL and LIPC genes was limited. This indicates that conclusions on the genetic causes of lipase activities outside of the normal range should be drawn with caution.