A mid-infrared laser-based sensor is designed and demonstrated for trace detection of benzene at ambient conditions. The sensor is based on a distributed feedback inter-band cascade laser operating near 3.3 μm and off-axis cavity-enhanced absorption spectroscopy. A multidimensional linear regression algorithm was applied to enable benzene measurements in the presence of interfering species, such as ethylene, methane and water vapor. A minimum detection limit of 2 ppb was achieved for benzene at an integration time of 6 seconds; the detection limit reduces to 200 ppt in dry conditions. A cross-sensitivity analysis was performed to study the effect of interfering species on benzene measurements. The sensor can be used to detect tiny leaks of benzene in petrochemical facilities and to monitor air quality in residential and industrial areas. The sensor performance was demonstrated by measuring air samples collected from various locations such as a petrol station, parking garage and ambient air.