Carpal tunnel syndrome (CTS) is the most common nerve entrapment syndrome. Electromyogram (EMG) is beneficial in supporting the diagnosis of CTS. We compared standard nerve conduction studies of EMG with median and ulnar motor nerve conduction studies from recordings of second lumbrical and interosseal muscles in supporting the diagnosis of CTS. In this study, a total of 242 patients were included, and a total of 375 hands were involved. Electrophysiologic CTSs were diagnosed in 283 hands of 161 patients. A significant association between second lumbrical-interosseal distal motor latency difference (2LI-MDLD) and CTS was found in this study. Statistically, every 0.1 increment in the 2LI-MDLD value was observed to increase the risk of disease by 1.74. When a cut-off of >= 0.5 for 2LI-MDLD is taken for predicting CTS, the sensitivity of the test is found to be 89.4% and specificity 84.4%. When the cut-off value for motor distal latency of second lumbrical of the median nerve (2L-MDL) was taken as >= 3.15 milliseconds in the diagnosis of CTS, the sensitivity of the test was 87.3%, and specificity 70.7%. Previous reports and our findings suggest that in CTS diagnosis, not only 2LI-MDLD value but also 2L-MDL value are easy and rapidly obtainable and offer additional information in very severe cases where compound muscle action potentials (CMAP) cannot be recorded from the abductor pollicis brevis (APB) muscle.