A new analytical method for multiresidue determination of 16 multiclass pesticides in lettuce was developed using ultra-high performance liquid chromatography with tandem mass spectrometry with a triple quadrupole mass analyzer and positive mode electrospray ionization, using a previously optimized quick, easy, cheap, effective, rugged, and safe method for sample preparation. Validation studies, according to document SANTE/11945/2015, demonstrated that the developed method is selective, accurate, and precise, providing recoveries of 70-120%, relative standard deviations ≤20% and quantification limits from 3 μg/kg. The method was compared with one based on high-performance liquid chromatography with tandem mass spectrometry, in terms of chromatographic performance, detectability and matrix effect for five varieties of lettuce. The new method provided a reduction in the time for the chromatographic analysis of 50%, from 30 to 15 min, using a lower mobile phase flow rate (0.147 mL/min), which reduced the consumption of mobile phase by 25%, and injection of smaller amounts of sample (1.7 μL). Lower limits of quantification were obtained for almost all pesticides studied for green-leaf lettuce. However, in relation to the matrix effect, four of the five types of lettuce studied presented higher matrix effects.