Aims: This study was carried out to evaluate the antibiotic susceptibility pattern and plasmid profiling of selected multi -drug resistant bacteria isolated from ear, nose and throat samples collected from two different hospitals in Cross River State. Methodology and results: One hundred two samples of wounds (53), throat (7), ear (11) and sputum (31) were collected from ambulatory patients in two hospitals in Cross River State. Standard microbiological analysis methods were used to examine the samples. The Kirby-Bauer disc diffusion method was used to conduct susceptibility studies. Zippy plasmid miniprep kits were used to extract the plasmid DNA. Ethidium bromide was used for plasmid curing. SSPS was used to analyze replicate data. Results suggest that 71.6% of the samples analyzed were positive for bacterial growth and 28.4% were negative. Bacterial species identified were Staphylococcus aureus, Proteus mirabilis, Klebsiella sp, Escherichia coli, Providencia sp., Pseudomonas aeruginosa, Enterobacter sp., Streptococcus pyogenes and Citrobacter sp. Over 60% of the isolates were resistant to antibiotics used, with augmentin having the highest while graxone recorded the least resistance rate. The plasmid analysis of the multi-drug resistant bacteria revealed 2-4 plasmids per bacterial cell with sizes ranging from 2.0-42.1 kb. The result of the plasmid curing showed that ethidium bromide is a potent plasmid curing agent as none of the genes was amplified.Conclusion, significance and impact of study: This study revealed that the prevalence of antibiotic resistance was alarmingly high in isolated bacteria. It also revealed that the resistance is plasmid-mediated. Therefore, it is important that the rational use of antibiotics be emphasized among the public.