Mosquito resistance to insecticides remains a growing concern in North Africa. The heavy reliance on insecticides and their recurrent and oftentimes inappropriate application are key sources for resistance, which is a potential threat to the global public health. Four populations of Culex pipiens pipiens were sampled from four areas of Tunisia, with the areas characterized by contrasting agricultural activity and usage of insecticides for vector control. Bioassays were performed to determine the level of resistance in each population to pirmiphos-methyl insecticide. Comparison of resistance ratios among the populations suggested a possible link of pirmiphos-methyl resistance with agricultural activity and insecticide usage. Little or no cross-resistance was observed with pirmiphos-methyl and either organophosphates or pyrethroids commonly used in those areas. Detoxification enzymes and target site (acetylcholinesterase) were involved in the observed resistance. Overall, the results of the present study suggest the role of insecticide usage and other activities in the immediate area in impacting the development of insecticide resistance in mosquitoes, with a possible major factor being agricultural activities.