The catalytically inactive form of lipoprotein lipase (LPL) is detectable at high levels in serum, although its physiologic role remains unknown. The aim of this study was to elucidate the clinical significance of serum LPL compared with postheparin LPL or the net increment (Delta) of LPL (postheparin - preheparin LPL). We measured the LPL mass before and 15 minutes after the injection of heparin in 164 subjects with hyperlipidemia. LPL mass was measured by a sensitive sandwich enzyme-linked immunosorbent assay (ELISA). Serum LPL was one fifth of the postheparin LPL concentration. There was a weak correlation between the serum LPL and postheparin LPL concentrations (r =.225, P </=.005). The Delta LPL concentration was strongly related to the postheparin LPL concentration (r =.965, P </=.0001), but not to the preheparin LPL mass, suggesting that the weak correlation between serum LPL and postheparin LPL levels was attributable to contamination of postheparin plasma by pre-existing LPL (preheparin LPL). Both serum and postheparin LPL were significantly lower in diabetic patients and in subjects with high levels of triglyceride or low levels of high-density lipoprotein (HDL). Serum LPL was correlated negatively with triglyceride, remnants, and insulin resistance and was positively correlated with HDL cholesterol and low-density lipoprotein (LDL) size. Postheparin LPL was strongly correlated with HDL cholesterol, but not with other parameters, as was serum LPL. Delta LPL mass did not show a closer association with triglyceride metabolism than postheparin LPL or preheparin LPL. In conclusion, serum LPL measurement is simple and seems to be useful for studying triglyceride metabolism.