Introduction Clostridium difficile (C. difficile) is one of the major causes of diarrheatransmitted by the fecal-oral route. C. difficiletype BI/NAP1/027is responsible for the most severe C. difficile infection (CDI). It is a major cause of antibiotic-associated diarrhea followed byClostridium perfringens,Staphylococcus aureus,andKlebsiella oxytoca. Historically, clindamycin, cephalosporins, penicillins, and fluoroquinolones were related to CDI. We conducted this study to evaluate the antibiotics associatedwith CDI in recent times. Methods We conducted a retrospective, single-center study over a period of eight years. A total of 58 patients were enrolled in the study. Patients withdiarrhea and positive C. difficile toxin in stool were evaluated for antibiotics given, age, presence of malignancy,previous hospital stay for more than three days in the last three months, and any comorbidities. Results Among patients who developed CDI, prior antibiotics for at least four days duration were given in 93% (54/58) of patients. The most common antibiotics associated with C. difficile infection were piperacillin/tazobactam in 77.60% (45/58), meropenem in 27.60% (16/58), vancomycin in 20.70% (12/58), ciprofloxacin in 17.20% (10/58), ceftriaxone in 16% (9/58), and levofloxacin in 14% (8/58) of patients, respectively. Seven percent (7%) of patients with CDI did not receive any prior antibiotics. Solid organ malignancy was present in67.20% and hematological malignancy in 27.60% of CDI patients. Ninety-eight percent (98%, 57/58) of patients treated with proton pump inhibitors, 93% of patients with a previous hospital stay for more than three days,24% of patients with neutropenia, 20.1% of patients aged more than 65 years, 14% of patients with diabetes mellitus, and 12%of patients with chronic kidney disease also developed C. difficile infection. Conclusion The antibiotics associated with C. difficile infection are piperacillin/tazobactam, meropenem, vancomycin, ciprofloxacin, ceftriaxone, and levofloxacin. Other risk factors for CDI are proton pump inhibitor use, prior hospital admission, solid organ malignancy, neutropenia, diabetes mellitus (DM), and chronic kidney disease (CKD).