High I/O density and green materials are the two major drivers of package substrates for flip-chip and 3D IC packaging. Future organic laminate substrates will require 5–25 μm lines and spaces and through-package-via (TPV) pitch of 50–100 μm. This ultra fine pitch requirement will lead to serious substrate failures due to electrochemical migration and conductive anodic filament (CAF). Therefore, there is a need to develop new halogen-free materials and investigate their reliability in ultra-fine pitch applications. This work focuses on four areas, 1) Advanced halogen-free materials, 2) Surface insulation resistance (SIR) in fine lines and spaces, 3) Conductive anodic filament (CAF) in fine-pitch TPVs, and 4) Flip-chip interconnection reliability. The substrate materials selected for this study include resin formulations that incorporate halogen-free flame retardants onto the polymer backbone. The SIR was studied on substrates with 50 μm spaced copper traces and CAF was studied with TPVs of 150 μm and 400 μm spacing. In both the tests, the halogen-free substrates were observed to show better electrochemical migration resistance in comparison to brominated FR-4. Flip-chip reliability was studied by subjecting the test substrates to Thermal Cycling Test (TCT), Unbiased-Highly Accelerated Stress Test (U-HAST) and High Temperature Storage (HTS) test. Scanning Acoustic Microscopy (C-SAM) analysis and electrical resistance measurements were performed after each of the reliability tests. The test substrates passed 200 hours of HTS, 96 hours of HAST and 2000 cycles in TCT respectively. The flip-chip reliability results indicate that these materials have the potential for replacing the conventional halogenated substrates for high density packaging applications.