Background: Mobile phones have become ubiquitous. There are concerns about possible health hazards posed by mobile phone-based radio frequency electromagnetic field (RF-EMF). Such exposure may be recognized as external stressor at molecular level which can be identified up by shot gun proteomics approach. Objective: To study molecular effects of mobile phone-based RF-EMF exposure using shot gun proteomics. Methods: 40 individuals (30 mobile phone users and 10 non-users) were recruited based on the inclusion and exclusion criteria. Mobile phone users had mobile phone usage of more than a year, an age group of 18-65 years with no major medical or surgical illness and normal results of hemogram, liver function tests (LFT), kidney function tests (KFT) and random/fasting sugars. Non-users had no mobile phone, Wi-Fi, and microwave usage. Both mobile phone users and non-users were non-alcoholic and non-smoker. RF-EMF exposure from mobile phone and miscellaneous sources was assessed using questionnaire. Calling-time duration per day was used as a measure of mobile phone exposure and the users were classified accordingly. Five biological replicates (1 set with both genders, 2 sets each of males and females) of proteomics experiments were designed. Human plasma samples were immunodepleted of high abundant proteins, concentrated, reduced, alkylated, digested, and labelled by i-TRAQ reagents for mass spectrometry analysis. Bioinformatics study was done on differentially expressed proteins for gene ontology (GO) classification, Protein-protein interactions (PPIs) and pathway enrichment. Results: The study group was quite young (median age 24 years). Pathway enrichment studies found Dopamine mediated receptor signaling, Adrenaline and Noradrenalin synthesis, Plasminogen activating cascade, Cholecystokinin receptor (CCKR) signaling, Gonadotropin-releasing hormone (GnRH) pathway and Vitamin-D signaling and its metabolism to be implicated. Conclusion: The involvement of the differentially expressed proteins in various signalling cascades have implications physiologically albeit large sample size studies incorporating non-users need to be conducted to draw out clear inferences.