Abstract Body (Do not enter title and authors here): Background: Inherited long QT syndromes (LQTS) predispose patients to life-threatening arrhythmias. The objective of study was to predict the efficacy of mexiletine in shortening QT intervals using lidocaine attenuation testing (LAT), treadmill exercise testing (TET) and head-up tilt table testing (HUTT). Research Questions/Hypothesis: Long-term efficacy of mexiletine is predictable by using LAT and TET but not HUTT. Methods: A cohort of 124 LQTS patients, including 34 LQT1, 59 LQT2, 16 LQT3, and 15 other types were evaluated using LAT (n=115), TET (n=68), and HUTT (n=54). QTc dynamics during LAT/TET and HUTT outcomes were analyzed. A positive LAT was defined as a QTc shortening ≥30 ms from this cohort. Results of TET were categorized as QTc changes immediate after exercise compared with before as lengthening (ΔQTc ≥20 ms), shortening (ΔQTc ≤−20 ms), or unchanged (|ΔQTc| <20 ms). Effective mexiletine treatment required QTc shortening ≥40 ms without cardiac arrhythmic events during follow-up. Results: Mexiletine significantly shortened QTc intervals in patients with LQT1, 2 and 3 (P<0.01). QTc shortening was observed during LAT across subtypes by 51.8±29.1 ms (P<0.01). Patients with LQT3 reached the peak QTc shortening faster than that in LQT2 (37.5 vs. 75.0 minutes, P<0.01). Maximum QTc shortening in LAT was correlated with baseline QTc (r=0.519, P<0.01) and accurately predicted the efficacy of mexiletine (AUC=0.838; cutoff=45 ms). The optimal LAT duration for predicting the efficacy of mexiletine was 45 minutes (AUC=0.814; cutoff=32 ms; sensitivity=92.2%). LAT-positive patients showed markedly higher treatment response than LAT-negative (66.7% vs. 5.9%, P<0.01). During TET, QTc lengthening predominated in LQT1 (100.0%) and other types (75.0%), while shortening occurred in LQT2 (57.9%) and unchanged QTc in LQT3 (62.5%). Patients with QTc shortening after exercise showed significantly greater response to mexiletine therapy than those with QTc lengthening (76.2% vs. 42.9%, P<0.05). HUTT showed no predictive value of mexiletine or subtype differences (P>0.05). Conclusion: LAT and TET are valuable tests for predicting mexiletine efficacy and subtype differentiation in patients with LQTS. Maximum QTc shortening ≥45 ms post-LAT (or ≥32 ms at 45 min) and QTc dynamics during TET optimize treatment of mexiletine, particularly for LQT2/LQT3. These findings advocate for subtypes-driven diagnostic protocols to enhance precised LQTS management.