Objective: To assess the cost-effectiveness of introducing pneumococcal polysaccharide and nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in the National Immunization Programme of Malaysia. This study compared introducing PHiD-CV (10 valent vaccine) with current no vaccination, as well as against the alternative 13-valent pneumococcal conjugate vaccine (PCV13). Methods: A lifetime Markov cohort model was adapted using national estimates of disease burden, outcomes of pneumococcal disease, and treatment costs of disease manifestations including pneumonia, acute otitis media, septicemia, and meningitis for a hypothetical birth cohort of 550,000 infants. Clinical information was obtained by review of medical records from four public hospitals in Malaysia from the year 2008 to 2009. Inpatient cost from the four study hospitals was obtained from a diagnostic-related group-based costing system. Outpatient cost was estimated using clinical pathways developed by an expert panel. The perspective assessed was that of the Ministry of Health, Malaysia. Results: The estimated disease incidence was 1.2, 3.7, 70, and 6.9 per 100,000 population for meningitis, bacteremia, pneumonia, and acute otitis media, respectively. The Markov model predicted medical costs of Malaysian ringgit (RM) 4.86 billion (US $1.51 billion) in the absence of vaccination. Vaccination with PHiD-CV would be highly cost-effective against no vaccination at RM30,290 (US $7,407) per quality-adjusted life-year gained. On comparing PHiD-CV with PCV13, it was found that PHiD-CV dominates PCV13, with 179 quality-adjusted life-years gained while saving RM35 million (US $10.87 million). Conclusions: It is cost-effective to incorporate pneumococcal vaccination in the National Immunization Programme of Malaysia. Our model suggests that PHiD-CV would be more cost saving than PCV13 from the perspective of the Ministry of Health of Malaysia.