In this contribution we present results from two individual gas monitoring experiments which were conducted during the drilling of the SAFOD (San Andreas Fault Observatory at Depth) boreholes. Gas from circulating drilling mud was monitored during the drilling the SAFOD III side tracks and was later analyzed for δ 13C (CH 4, C 2H 6 and C 3H 8), H/D (CH 4) and noble gas isotopes. Furthermore, gas accumulations induced by drill pipe retrieval (“trip gas”) from the SAFOD MH and the SAFOD III boreholes were also investigated. The data are interpreted in the context of gas migration processes and the permeability structure of the San Andreas Fault (SAF) around two actively deforming zones at 3194 m and 3301 m borehole depth. Helium isotope ratios of 0.86 R a at 3203 m and between 0.51 and 0.88 R a at 3262 m (R a is the atmospheric 3He/ 4He ratio) indicate an improved flow of mantle volatiles between both fault strands. Much lower values were observed at 3147 m (0.26 R a) and 3312 m (0.22 R a). Hydrocarbon concentrations coincide with the occurrence of shale at ~ 3150–3200 m and below ~ 3310 m depth. The molecular and isotope composition of hydrocarbons and their spatial distributions imply hydrocarbon generation by thermal degradation of organic matter followed by extensive diffusion loss. Carbon isotope data furthermore suggest a thermal maturity of the source rock of approx. 1.4%R 0. The concentration of trip gas is generally low in the interval 3100 m–3450 m but exhibits high spatial variability. At 3128 m and 3223 m depth, the trip gas concentrations are as low as in the granite section of the SAFOD Main Hole. Considerable variations of R a values, trip gas concentrations, and the molecular composition of hydrocarbons when penetrating the active fault strands let us conclude that the permeability of the fault transverse to the fault direction is limited and that the active fault has not been breached over many earthquake cycles such that little or no fluid exchange took place. Diffusion is the dominant mechanism controlling hydrocarbon migration through the fault strands. The elevated R a values between both fault strands may reflect either episodic or continuous flow of mantle-derived fluids, suggestive of some limited permeability parallel to the fault direction.